Self-emulsifying composition of omega3 fatty acid

ABSTRACT

A self-emulsifying composition contains: 70 to 90% by weight of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters; 0.5 to 6% by weight of water; 1 to 29% by weight of a polyoxyethylene sorbitan fatty acid ester as an emulsifier (optionally including a polyoxyl castor oil, and not including lecithin); and lecithin in an amount of 3 to 40 parts by weight in relation to 100 parts by weight of ω3 polyunsaturated fatty acids and the like. The self-emulsifying composition is excellent in self-emulsifying property, composition dispersibility, emulsion stability, and absorbability, is free from ethanol and polyhydric alcohols or only has such an alcohol added thereto at a reduced concentration, and is useful for foods and pharmaceuticals.

TECHNICAL FIELD

This invention provides a self-emulsifying composition containing atleast one member selected from the group consisting of ω3polyunsaturated fatty acids and their pharmaceutically acceptable saltsand esters. This invention also provides its pharmaceutical product, itsproduction method, a therapeutic method using such pharmaceuticalproduct, and a method for using the same.

BACKGROUND ART

Known ω3 polyunsaturated fatty acids (hereinafter abbreviated as ω3PUFA) include α-linolenic acid, eicosapentaenoic acid (hereinafterabbreviated as EPA), and docosahexaenoic acid (hereinafter abbreviatedas DHA). Since the ω3 PUFA and pharmaceutically acceptable salts andesters thereof (hereinafter abbreviated as ω3 PUFA) have actions such asanti-arteriosclerosis action, platelet aggregation suppressive action,blood lipid lowering action, anti-inflammatory action, carcinostaticaction, and central action, they are blended in various food products,and commercially sold in the form of health food and medical andpharmaceutical products.

Ethyl eicosapentaenoate ester (hereinafter abbreviated as EPA-E) iscommercially sold in Japan as an oral therapeutic agent for amelioratingulcer, pain, and coldness associated with arteriosclerosis obliterans(hereinafter abbreviated as ASO) as well as hyperlipidemia (product nameEpadel, Mochida Pharmaceutical Co., Ltd.). When EPA-E is orallyadministered under fasting, increase in plasma EPA concentration issmaller than the case of the oral administration after the mealconceivably because absorption of the EPA-E requires secretion of bileacid and food components as a carrier. Accordingly, Epadel is instructedto be orally administered after the meal (see Non-Patent Literature 1).

However, dosage method or drug compliance has become a problem for thosepeople not taking breakfast with the recent change in the life style,patients who can only take meals at a reduced amount, patients who canonly take a fluid diet (milk, rice broth, starch gruel, egg, soup,juice, or oral nutritional supplement), patients with reduced absorptionability of the intestinal tract (for example, elderly, patients ofintestinal disease, patients after intestinal surgery, terminal cancerpatients, and patients taking a lipase inhibitor), or patients who areunable to take meals such as those after the cerebral infarction.

Attention is also being given to the relation between thehypertriglyceridemia in non-fasting conditions wherein serumtriglyceride (hereinafter abbreviated as TG) that had been normal infasting conditions exhibits abnormal increase after the meal and suchcondition is retained for a while and coronary artery diseases, andaccordingly, there is a demand for an ω3PUFA preparation which israpidly absorbed by pre-meal administration to suppress the increase ofthe post-meal increase of the serum TG.

A self-emulsifying preparation which does not contain water in thepreparation and which is readily dispersible and self-emulsifying whenbrought in contact with water has been reported (see Patent Literature 1and Non-Patent Literature 4). This preparation contains an ω3 PUFA andfenofibrate as its effective components, ethanol, and a surfactant.

These compositions contain ethanol as a component added for improvingthe dissolution of the fenofibrate. However, volatilization of theethanol is associated with the risk of capsule deformation and bubbleinclusion in the capsule, damages in the quality such as capsuledeformation and cracks, as well as denaturing of the content in thecapsule such as cloudiness and separation. In addition, use of apreparation containing such composition should be impossible ordifficult if not impossible for patients intolerable for the alcohol(ethanol).

A self-emulsifying composition containing ethanol and polyhydricalcohols in addition to the ω3 PUFA and a surfactant which is capable offorming a dispersion having a small or very small average particle sizewhen brought in contact with water is also reported (Patent Literature2).

With regard to self-emulsifying compositions having a low ethanolcontent, a self-emulsifying composition comprising an ω3 PUFA, anemulsifier having a hydrophile lipophile balance (hereinafterabbreviated as HLB) of at least 10, lecithin, and a polyhydric alcoholsuch as propylene glycol or glycerin which has high self-emulsifyingproperty, oral fasting absorbability and absorption speed has beenreported (Patent Literature 3).

A self-emulsifying composition containing an ω3PUFA ester and asurfactant but not containing ω3PUFA free acid, which is not affected bymeal has been reported (Patent Literature 4). However, the compositionin which EPA-E is mainly contained as the ω3PUFA ester is not examined.

When a composition containing a co-solvent such as a polyhydric alcoholis encapsulated in a capsule, the co-solvent moves to the capsule filmto cause denaturing of the composition as well as capsule deformationdue to the softening of the capsule (Patent Literature 5).

Self-emulsifying compositions, as generally containing larger amounts ofemulsifiers and, accordingly, being increased in total amount, areliable to cause inflammation of the gastrointestinal tract or have areduced content per capsule of the biologically active componentdissolved in oil component (Patent Literature 6). Accordingly, theemulsifier used in the self-emulsifying composition is preferably theone which is non-toxic or less-toxic even in the case of continuousadministration, and the emulsifier is preferably used at a low content.

In view of compliance, amount of the emulsifier and alcoholsincorporated should be minimized also in consideration of reducing thesize of the preparation because amount of the preparation that has to betaken per administration increases with the increase in the amount ofthe components other than the ω3 PUFA in the self-emulsifyingcomposition since predetermined amount of the ω3 PUFA should be takenper administration.

CITATION LIST Patent Literatures

-   [Patent Literature 1] JP 2008-516890 A-   [Patent Literature 2] JP 2012-519728 A-   [Patent Literature 3] WO 2010/134614-   [Patent Literature 4] WO 2013/148136-   [Patent Literature 5] JP 2011-12003 A-   [Patent Literature 6] JP 2012-180337 A

Non-Patent Literatures

-   [Non-Patent Literature 1] Epadel S (Drug Interview Form), Mochida    Pharmaceutical Co., Ltd., June, 2012-   [Non-Patent Literature 2] “Guideline for Diagnosis and Prevention of    Atherosclerotic Cardiovascular Diseases, 2007 Edition” edited by    Japan Atherosclerosis Society and published by Kyowa Kikaku Ltd.,    Apr. 25, 2007-   [Non-Patent Literature 3] Diabetes, vol. 57, no. 9, 2382-2392, 2008-   [Non-Patent Literature 4] European Journal of Pharmaceutical    Sciences, vol. 33, 351-360, 2008-   [Non-Patent Literature 5] “2007 Dictionary of Drug Additives” edited    by International Pharmaceutical Excipients Council Japan and    published by Yakuji Nippo Ltd., Jul. 25, 2007

SUMMARY OF INVENTION Technical Problems

There is a demand for a preparation wherein amount of the ethanol andpolyhydric alcohol in the self-emulsifying composition has been reduced.

There is also a demand for a preparation wherein amount of theemulsifier in the self-emulsifying composition has been reduced.

There is also a demand for a preparation wherein amount of the ω3PUFA inthe self-emulsifying composition has been increased.

There is also a demand for a preparation with improved safety foranimals (including human).

There is also a demand for a self-emulsifying composition with excellentdrug compliance.

There is also a demand for a self-emulsifying composition which canretain its good appearance without exhibiting denaturing such ascloudness or separation if stored at room temperature. There is also ademand for a self-emulsifying composition which is excellent in at leastone of compatibility (appearance), self-emulsifying property,dispersibility of the composition, emulsion stability, andabsorbability.

There is also a demand for a self-emulsifying composition which canretain its good appearance without exhibiting denaturing such ascloudiness or separation even if stored in low or high temperatureconditions in addition to the room temperature since theself-emulsifying composition may be stored in cold area in its use as adrug. There is also a demand for a self-emulsifying composition which isexcellent in at least one of compatibility (appearance),self-emulsifying property, dispersibility of the composition, emulsionstability, and absorbability.

There is also a demand for a self-emulsifying composition which hasstorage stability at at least one of room temperature, low temperatureand high temperature.

There is also a demand for a self-emulsifying composition which hasstorage stability at at least one specific temperature selected from thetemperature of from, for example, 5° C. to 40° C.

There is also a demand for a self-emulsifying composition which does notchange the parameters to cause stable quality as a pharmaceuticalproduct deteriorate if stored at at least one of room temperature, lowtemperature and high temperature.

There is also a demand for a self-emulsifying composition which does notchange the parameters to cause stable quality as a pharmaceuticalproduct to deteriorate if stored at at least one specific temperatureselected from the temperature of from, for example, 5° C. to 40° C.

There is also a demand for a preparation wherein the composition hasbeen encapsulated.

There is also a demand for a preparation wherein softening of thecapsule film in the encapsulation of the composition has been suppressedso that the preparation is not deformed.

There is also a demand for a self-emulsifying composition with improvedabsorption of the ω3PUFA.

There is also a demand for a self-emulsifying composition which exhibitsthe same pharmacokinetics as the conventional pharmacokineticsimmediately after the post-meal administration of the ω3PUFA preparationeven if administered at a smaller dose of the ω3PUFA.

There is also a demand for a self-emulsifying composition which has hightherapeutic effects, or by which the dose of the ω3PUFA required for thetreatment can be reduced.

There is also a demand for a self-emulsifying composition whichincreases the ω3PUFA concentration in blood (the term “in blood” means“in whole blood, plasma, or serum” and this also applies to thefollowing description) after the administration of the self-emulsifyingcomposition as well as a method for such increase.

There is also a demand for a self-emulsifying composition which israpidly absorbed even if administered before the meal or after thelow-fat meal to thereby suppress an increase in the serum TG as well asa method for such suppression.

There is also a demand for a self-emulsifying composition which preventsessential fatty acid deficiency upon administration of the lipaseinhibitor as administered before going to bed as well as a method forsuch prevention.

There is also a demand for a self-emulsifying composition which canreduce the amount of the ω3PUFA that is not absorbed and then egestedafter administration as well as a method for such reduction.

There is also a demand for a self-emulsifying composition which enhancestissue migration properties of the ω3PUFA as well as a method for suchenhancement.

There is also a demand for a self-emulsifying composition with increaseduptake of the ω3PUFA into phospholipid in blood as well as a method forsuch increase.

There is also a demand for a self-emulsifying composition whichdecreases arachidonic acid in blood and/or improves the EPA/AA ratioindicating the ratio of EPA to arachidonic acid as well as a method forsuch decrease and/or improvement.

There is also a demand for a self-emulsifying composition with reducedside effects (side effects of lower gastrointestinal tract, nausea,abdominal discomfort, diarrhea, abdominal pain, heartburn, vomiting,anorexia, constipation, stomatitis, thirst, bloating, flatulence, etc.)as well as a method for such reduction.

There is also a demand for a self-emulsifying composition whereinabsorption of the ω3PUFA is not or little affected by the meal as wellas a method thereof.

There is also a demand for a self-emulsifying composition which exhibitsgood absorption of the ω3PUFA irrespective of timing of theadministration whether the administration is carried out in the fasting,before the meal, or after the low-fat meal.

There is also a demand for a self-emulsifying preparation or a methodwhich is capable of: by administration, improving (reducing) at leastone parameter selected from TG, total cholesterol (hereinafter referredto as T-cho), low density lipoprotein cholesterol (hereinafter referredto as LDL-C), non-high density lipoprotein cholesterol (hereinafterreferred to as non-HDL-C), very low density lipoprotein cholesterol(hereinafter referred to as VLDL-C), very low density lipoproteintriglyceride (hereinafter referred to as VLDL-TG), oxidized low densitylipoprotein (hereinafter referred to as oxidized LDL), small dense LDL,hyper-remnant-like lipoprotein particle cholesterol (hereinafterreferred to as RLP-C), apoprotein B (hereinafter referred to as ApoB),apolipoprotein CIII (hereinafter referred to as ApoCIII), lipoprotein(a), lipoprotein-associated phospholipase A2 (hereinafter referred to asLp-PLA2), cholesteryl ester transfer protein (hereinafter referred to asCETP activity), high-sensitivity C-reactive protein (hereinafterreferred to as hs-CRP), plasma phospholipid, free fatty acid, fastingblood glucose, hyper-hemoglobin A1c (hereinafter referred to as HbA1c),hyper insulin resistance index (hereinafter referred to as HOMA-IR),intercellular adhesion molecule-1, interleukin-6 (hereinafter referredto as IL-6), plasminogen activator inhibitor-1 (hereinafter referred toas PAI-1), creatinine, aspartic acid aminotransferase (hereinafterreferred to as AST), alanineaminotranspherase (hereinafter referred toas ALT), uric acid, 8-isoprostane, thromboxane A2 (hereinafter referredto as TXA2) and leukotriene B2 (hereinafter referred to as LTB2) and themetabolites thereof (hydroxy eicosatetraenoic acid (hereinafter referredto as HETE)), and the like; improving (increasing) at least oneparameter selected from high density lipoprotein cholesterol(hereinafter referred to as HDL-C), apoprotein A-I (hereinafter referredto as apoA-I), apoA-I/ApoB ratio, EPA in the plasma, serum, erythrocytemembrane or platelet membrane; reducing the number of LDL particles;increasing LDL particle size; and improving at least one parameterselected from apoprotein E (hereinafter referred to as ApoE) genotypeabnormality, hemoglobin abnormality, hematocrit abnormality, thrombocyteabnormality, and the like.

There is also a demand for a self-emulsifying composition which can beabsorbed even when administered at a high dose at the level that theabsorption of the ω3PUFA would be saturated with no further absorptionin blood if the ω3PUFA were solely administered.

There is also a demand for a self-emulsifying composition wherein thecomposition has stable quality.

There is also a demand for a self-emulsifying composition which hasstorage stability immediately after its production or for any longperiod of, for example, three or five years after its production.

There is also a demand for a self-emulsifying composition which does notchange the parameters to cause stable quality as a pharmaceuticalproduct deteriorate immediately after its production or if stored forany long period of, for example, three or five years after itsproduction.

There is also a demand for an emulsion with improved absorption of theω3PUFA, a self-emulsifying composition for enabling quick production ofthe emulsion, and a method for producing the emulsion.

Accordingly, an object of the present invention is to provide aself-emulsifying composition which is capable of solving at least one ofthe problems as described above, a preparation encapsulating suchcomposition, a therapeutic method using such preparation, and a methodfor using such preparation.

Solution to Problems

In view of the situation as described above, the inventors of thepresent invention conducted an intensive investigation on componentswhich can substitute the ethanol and polyhydric alcohol and found that apredetermined amount of water is useful for improving compatibility ofthe self-emulsifying composition.

The inventors also found that since the content of water in thecomposition can be reduced to 0.5 to 6% by weight which is lower thanthe case of ethanol and polyhydric alcohol, and the content of theemulsifier can be further reduced by the improvement in compatibilitycaused by this small amount of water, production of a self-emulsifyingcomposition having high content the ω3PUFA is thereby enabled.

The inventors also found that a self-emulsifying composition which isexcellent in at least one of the objects as described above can beproduced, and the present invention was thereby completed.

The inventors also found that content of the emulsifier can be furtherreduced and the present invention of the self-emulsifying compositionhaving a high content of ω3PUFA was thereby completed.

The inventors also found that incorporation of the particular emulsifierenables production of a self-emulsifying composition which is favorablein at least one of higher blood concentration of the ω3PUFA, reducedside effects, absorption of the ω3PUFA not or least affected by themeal, unsaturation in the amount of the ω3PUFA absorption, and the like,and the present invention was thereby completed.

The composition of the present invention is a composition which isexcellent in at least one of the aspects as described above.

The first aspect of the present invention is the self-emulsifyingcomposition as described below.

(1-1) A self-emulsifying composition characterized in that, when thetotal amount of the self-emulsifying composition is 100% by weight, itcomprises

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of an emulsifier (not including lecithin), whichis preferably polyoxyethylene sorbitan fatty acid ester, and

d) lecithin at an amount of 3 to 40 parts by weight, or 1 to 25 parts byweight in relation to 100 parts by weight of ω3 polyunsaturated fattyacids or their pharmaceutically acceptable salts and esters, wherein

e) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe total composition.

(1-2) A self-emulsifying composition characterized in that, when thetotal amount of the self-emulsifying composition is 100% by weight, itcomprises

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 PUFA and their pharmaceutically acceptable salts andesters,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of an emulsifier which is preferablypolyoxyethylene sorbitan fatty acid ester, and

d) lecithin at an amount of 3 to 40 parts by weight, or 1 to 25 parts byweight in relation to 100 parts by weight of at least one compoundselected from the group consisting of ω3 polyunsaturated fatty acids andtheir pharmaceutically acceptable salts and esters, and

e) content of ethanol is up to 4% by weight of the total composition,and

f) content of polyhydric alcohol is up to 4-% by weight of the totalcomposition.

(1-3) A self-emulsifying composition according to the above (1-1) or(1-2) wherein the polyoxyethylene sorbitan fatty acid ester is at leastone member selected from the group consisting of polyoxyethylene (20)sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan tristearate, polyoxyethylene (20) sorbitan monoisostearate,polyoxyethylene (20) sorbitan monooleate, and polyoxyethylene (20)sorbitan trioleate.(1-4) A self-emulsifying composition according to any one of the above(1-1) to (1-3) wherein the emulsifier further comprises polyoxyethylenehydrogenated castor oil and/or polyoxyethylene castor oil.(1-5) A self-emulsifying composition according to any one of the above(1-1) to (1-4) wherein the emulsifier further comprises polyoxyethylenecastor oil.(1-6) A self-emulsifying composition according to any one of the above(1-1) to (1-5) wherein the polyhydric alcohol is propylene glycol orglycerin.(1-7) A self-emulsifying composition according to any one of the above(1-1) to (1-6) wherein the polyhydric alcohol content in the compositionis 0 to 4% by weight.(1-8) A self-emulsifying composition according to any one of the above(1-1) to (1-6) wherein the polyhydric alcohol content in the compositionis not in excess of 4% by weight.(1-9) A self-emulsifying composition according to any one of the above(1-1) to (1-8) wherein the polyhydric alcohol content in the compositionis up to 1% by weight.(1-10) A self-emulsifying composition according to any one of the above(1-1) to (1-9) wherein the polyhydric alcohol content in the compositionis 0 to 1% by weight,(1-11) A self-emulsifying composition according to any one of the above(1-1) to (1-8) wherein the polyhydric alcohol content in the compositionis not in excess of 1% by weight.(1-12) A self-emulsifying composition according to any one of the above(1-1) to (1-11) wherein the composition is substantially free from thepolyhydric alcohol.(1-13) A self-emulsifying composition according to any one of the above(1-1) to (1-12) wherein the ethanol content in the composition is up to4% by weight.(1-14) A self-emulsifying composition according to any one of the above(1-1) to (1-12) wherein the ethanol content in the composition is 0 to4% by weight.(1-15) A self-emulsifying composition according to any one of the above(1-1) to (1-12) wherein the ethanol content in the composition is not inexcess of 4% by weight.(1-16) A self-emulsifying composition according to any one of the above(1-1) to (1-15) wherein the composition is substantially free from theethanol.(1-17) A self-emulsifying composition according to any one of the above(1-1) to (1-16) wherein the ω3PUFA and their pharmaceutically acceptablesalts and esters are at least one member selected from the groupconsisting of EPA, DHA, and their pharmaceutically acceptable salts andesters.(1-18) A self-emulsifying composition according to any one of the above(1-1) to (1-17) wherein the ω3PUFA ester is ethyl ester or triglycerideester.(1-19) A self-emulsifying composition according to any one of the above(1-1) to (1-18) wherein the ω3PUFA and their pharmaceutically acceptablesalts and esters are EPA-E or ethyl ester of DHA (hereinafter referredto as DHA-E).(1-20) A self-emulsifying composition according to any one of the above(1-1) to (1-19) wherein the composition contains the at least one memberselected from the group consisting of EPA, DHA, and theirpharmaceutically acceptable salts and esters as its effective component.(1-21) A self-emulsifying composition according to any one of the above(1-1) to (1-20) wherein the composition contains EPA-E and/or DHA-E asits effective component.(1-22) A self-emulsifying composition according to any one of the above(1-1) to (1-21) containing EPA-E as its effective component.(1-23) A self-emulsifying composition according to any one of the above(1-1) to (1-22) wherein the lecithin is at least one member selectedfrom the group consisting of soybean lecithin, zymolytic soybeanlecithin, hydrogenated soybean lecithin, and egg yolk lecithin.(1-24) A self-emulsifying composition according to any one of the above(1-1) to (1-23) wherein content of at least one emulsifier selected fromthe group consisting of polyoxyethylene hydrogenated castor oil,polyethylene glycol fatty acid ester, and polyoxyethylenepolyoxypropylene glycol is less than 5% by weight of total amount of thecomposition. And also, the self-emulsifying composition according to anyone of the above (1-1) to (1-23) wherein content of each of theemulsifiers, namely, polyoxyethylene hydrogenated castor oil,polyoxyethylene glycol fatty acid ester, and polyoxyethylenepolyoxypropylene glycol is less than 5% by weight of total amount of thecomposition.(1-25) A self-emulsifying composition according to any one of the above(1-1) to (1-24) characterized in that a) to d) are mixed in any order.(1-26) A self-emulsifying composition according to any one of the above(1-1) to (1-25) wherein the composition has transparent appearance whenit is allowed to stand.(1-27) A self-emulsifying composition according to any one of the above(1-1) to (1-25) wherein the composition has an appearance withoutseparation or cloudiness when it is allowed to stand.(1-28) A self-emulsifying composition according to any one of the above(1-1) to (1-27) wherein the composition has transparent appearance whenit is stored in the environment of 5° C. or 40° C. for 12 hours.(1-29) A self-emulsifying composition according to any one of the above(1-1) to (1-28) wherein the composition has an appearance withoutseparation or cloudiness when it is stored in the environment of 5° C.or 40° C. for 12 hours.(1-30) A self-emulsifying composition according to any one of the above(1-1) to (1-29) wherein the composition is excellent in at least one ofself-emulsifying property, dispersibility of the composition, andemulsion stability.(1-31) A self-emulsifying composition according to any one of the above(1-1) to (1-30) wherein the composition emulsifies by itself when 10 μLof the composition is added dropwise to 5 ml of purified water or firstsolution of the dissolution test of Japanese Pharmacopeia at 37° c.(1-32) A self-emulsifying composition according to any one of the above(1-1) to (1-31) wherein the composition disperses by stirring when 10 μLof the composition is added dropwise to 5 ml of purified water or firstsolution of the dissolution test of Japanese Pharmacopeia at 37° C.(1-33) A self-emulsifying composition according to any one of the above(1-1) to (1-32) wherein the composition does not experience separationof oil when 10 μL of the composition is added dropwise to 5 ml ofpurified water or first solution of the dissolution test of JapanesePharmacopeia at 37° c.(1-34) A self-emulsifying composition according to any one of the above(1-1) to (1-33) wherein, when the self-emulsifying composition accordingto any one of the above (1-1) to (1-33) at an amount in terms of the atleast one compound selected from the group consisting of ω3PUFA andtheir pharmaceutically acceptable salts and esters of 600 mg is orallyadministered to each male beagle under the condition of at least 18hours of fasting, and the plasma ω3PUFA concentration is calculated byconducting the correction by subtracting ω3PUFA concentration in plasmabefore the administration, the maximum plasma ω3PUFA concentration (alsoreferred to as the maximum blood concentration) is at least 50 μg/ml,and/or the area under the curve of the plasma ω3PUFA concentration at 0to 2 hours after the administration is at least 30 μg·hr/mL; the maximumplasma ω3PUFA concentration is at least 50 μg/ml, and/or the area underthe curve of the plasma ω3PUFA concentration at 0 to 2 hours after theadministration is at least 50 μg·hr/mL; the maximum plasma ω3PUFAconcentration is at least 60 μg/ml, and/or the area under the curve ofthe plasma ω3PUFA concentration at 0 to 2 hours after the administrationis at least 60 μg·hr/mL; or the maximum plasma ω3PUFA concentration isat least 70 μg/ml, and/or the area under the curve of the plasma ω3PUFAconcentration at 0 to 2 hours after the administration is at least 70μg·hr/mL.(1-35) A self-emulsifying composition according to any one of the above(1-1) to (1-33) wherein, when the self-emulsifying composition at anamount in terms of the at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters of 45 mg/kg body weight is orally administered to each malecynomolgus monkey under the condition of at least 12 hours of fasting,and the plasma ω3PUFA concentration is calculated by conducting thecorrection by subtracting ω3PUFA concentration in plasma before theadministration, the maximum plasma ω3PUFA concentration is at least 50μg/ml, and/or the area under the curve of the plasma ω3PUFAconcentration at 0 to 12 hours after the administration is at least 400μg·hr/mL; or the maximum plasma ω3PUFA concentration is at least 70μg/ml, and/or the area under the curve of the plasma ω3PUFAconcentration at 0 to 12 hours after the administration is at least 500μg·hr/mL.(1-36) Use of the self-emulsifying composition according to any one ofthe above (1-1) to (1-33) wherein, when self-emulsifying compositionaccording to any one of the above (1-1) to (1-33) is orally administeredat an amount in terms of the at least one compound selected from thegroup consisting of ω3PUFA and their pharmaceutically acceptable saltsand esters of one selected from the group consisting of 500 mg, 1000 mg,1800 mg, 2000 mg, 3600 mg, 4000 mg, 6000 mg, and 8000 mg to each humanbefore the meal, the maximum plasma ω3PUFA concentration calculated byconducting the correction by subtracting the plasma ω3PUFA concentrationbefore the administration is at least 50 μg/mL and/or the plasma ω3PUFAconcentration 2 hours after the administration is at least 10 μg/mL.(1-37) A self-emulsifying composition according to any one of the above(1-1) to (1-33) wherein, when self-emulsifying composition according toany one of the above (1-1) to (1-33) is orally administered at an amountin terms of the at least one compound selected from the group consistingof ω3PUFA and their pharmaceutically acceptable salts and esters of oneselected from the group consisting of 500 mg, 1000 mg, 1800 mg, 2000 mg,3600 mg, 4000 mg, 6000 mg, and 8000 mg to each human before the meal,and the plasma ω3PUFA concentration is calculated by conducting thecorrection by subtracting ω3PUFA concentration in plasma before theadministration, the maximum plasma ω3PUFA concentration is at least 10μg/mL and/or the area under the curve of the plasma ω3PUFA concentrationat 0 to 72 hours after the administration is at least 250 μg·hr/mL.(1-38) A self-emulsifying composition according to (1-1) to (1-37)wherein the polyoxyethylene castor oil is up to 120 parts by weight inrelation to 100 parts by weight of the polyoxyethylene sorbitan fattyacid ester in the composition.(1-39) A self-emulsifying composition characterized in that, when thetotal amount of the self-emulsifying composition is 100% by weight, itcomprises

a) 70 to 90% by weight of EPA-E,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of an emulsifier which is polyoxyethylene sorbitanfatty acid ester, and

d) lecithin at an amount of 3 to 40 parts by weight, or 1 to 25 parts byweight in relation to 100 part by weight of the EPA-E, and

e) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe total composition.

(1-40) A self-emulsifying composition characterized in that, when thetotal amount of the self-emulsifying composition is 100% by weight, itcomprises

a) 70 to 90% by weight of EPA-E,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of an emulsifier which is polyoxyethylene sorbitanfatty acid ester, and

d) lecithin at an amount of 3 to 40 parts by weight, or 1 to 25 parts byweight in relation to 100 part by weight of the EPA-E, and

e) content of ethanol is up to 4% by weight of the total composition,and

f) content of polyhydric alcohol is up to 4% by weight of the totalcomposition.

The second aspect of the present invention is the capsulatedself-emulsifying preparation as described below.

(2-1) A self-emulsifying capsule preparation wherein the content is theself-emulsifying composition according to any one of the above (1-1) to(1-40) and wherein the composition is encapsulated by a hard capsuleand/or a soft capsule.(2-2) A self-emulsifying capsule preparation according to (2-1) havinggood hardness immediately after its production.(2-3) A self-emulsifying capsule preparation according to (2-1) or (2-2)having a hardness of at least 18 kgf immediately after its production.(2-4) A self-emulsifying capsule preparation according to any one of(2-1) to (2-3), wherein, when the preparation is sealed in an aluminumpackage and stored at 40° C. for 1 week, the preparation does notexperience loss of hardness of 6 kgf or more compared with the hardnessbefore the storage.(2-5) A self-emulsifying capsule preparation according to any one of(2-1) to (2-4) wherein, when the preparation is sealed in an aluminumpackage and stored at 40° C. for 1 week, the preparation retains ahardness of at least 20 kgf.(2-6) A self-emulsifying capsule preparation according to any one of(2-1) to (2-5) wherein, when the preparation is sealed in an aluminumpackage and stored at 40° C. for 1 week, the hardness after the storageis more than 60% of the hardness before the storage.(2-7) A preparation according to any one of the above (2-1) to (2-6)which is at least one member selected from the group consisting oftherapeutic agents for dyslipidemia (hypercholesterolemia, hyper-LDLcholesterolemia, hyper-non-HDL cholesterolemia, hyper-VLDLcholesterolemia, hypo-HDL cholesterolemia, hypertriglyceridemia,hyper-ApoB-emia, hypo-ApoAI-emia, increased LDL particle number-emia,small LDL particle size-emia, hyper-oxidized LDL-emia, hyper-small denseLDL-emia, hyper-RLP-C-emia, hypo-apoA-I/ApoB ratio-emia,hyper-ApoCIII-emia, dys-ApoE genotype-emia, hyper-lipoprotein (a)-emia,hyper-Lp-PLA2-emia, hyper-CETP activity-emia, hyper-hs-CRP-emia,hypo-EPA-emia (the state wherein EPA value in plasma, serum, erythrocytemembrane, platelet membrane is low), hyper-free fatty acidemia),hyper-fasting glucose-emia, hyper-HbA1c-emia, hyper-HOMA-IR-emia,hyper-intercellular adhesion molecule-1-emia, hyper-IL-6-emia,hyper-PAI-1-emia, hypercreatininemia, hyper-AST-emia, hyper-ALT-emia,hyper-uric acidemia, hyper-8-isoprostane-emia, hyper-TXA2-emia,hyper-LTB2-emia, etc., therapeutic agent for postprandial hyperglycemia,antiarteriosclerotic agent, platelet aggregation suppressive agent,therapeutic agent for peripheral circulatory insufficiency, agent forpreventing onset of cardiovascular events, therapeutic agent forinflammatory diseases (nonalcoholic fatty liver disease (hereinafterreferred to as NAFLD), non-alcoholic steatohepatitis (hereinafterreferred to as NASH), etc.), progression suppressant and therapeuticagent of dementia (Alzheimer-type dementia, vascular dementia,mixed-type dementia, etc.), anticancer agent, and preventive andtherapeutic agents and progression suppressant for central diseases(depression, depressive state, obsessive-compulsive disorder, socialphobia, panic disorder, etc.).

The third aspect of the present invention is the method for producingthe self-emulsifying composition as described below.

(3-1) A method for producing a self-emulsifying composition comprisingthe step of, when the total amount of the self-emulsifying compositionis 100% by weight, mixing the following components a) to d) in any order

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of an emulsifier which is polyoxyethylene sorbitanfatty acid ester, and

d) lecithin at an amount of 3 to 40 parts by weight or 1 to 25 parts byweight in relation to 100 parts by weight of at least one compoundselected from the group consisting of ω3 polyunsaturated fatty acids ortheir pharmaceutically acceptable salts and esters, wherein

e) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe total composition.

(3-2) A method for producing a self-emulsifying composition comprisingthe step of, when the total amount of the self-emulsifying compositionis 100% by weight, mixing the following components a) to d) in any order

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3 PUFA and their pharmaceutically acceptable salts andesters,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of an emulsifier which is polyoxyethylene sorbitanfatty acid ester, and

d) lecithin at an amount of 3 to 40 parts by weight in relation to 100parts by weight of ω3 polyunsaturated fatty acids or theirpharmaceutically acceptable salts and esters, wherein

e) content of ethanol is up to 4% by weight of the total composition,and

f) content of polyhydric alcohol is up to 4% by weight of the totalcomposition.

(3-3) A method for producing a self-emulsifying composition according to(3-1) or (3-2) wherein the method includes the step of mixing the a), b)and/or c) of the step as described above under heating to 70° c.

The fourth aspect of the present invention is a drug for administeringthe self-emulsifying composition by particular route.

(4-1) A preparation for orally administering the self-emulsifyingcomposition or capsulated self-emulsifying preparation, drug orveterinary drug according to any one of the above (1-1) to (1-40) and(2-1) to (2-7) in the fasting or before going to bed.(4-2) A preparation for orally administering the self-emulsifyingcomposition or capsulated self-emulsifying preparation, drug orveterinary drug produced by the production method according to any oneof the above (3-1) to (3-3) in the fasting or before going to bed.(4-3) A preparation according to the above (4-1) or (4-2) wherein thedrug is at least one member selected from the group consisting oftherapeutic agent for dyslipidemia (hypercholesterolemia, hyper-LDLcholesterolemia, hyper-non-HDL cholesterolemia, hyper-VLDLcholesterolemia, hypo-HDL cholesterolemia, hypertriglyceridemia,hyper-ApoB-emia, hypo-ApoAI-emia, increased LDL particle number-emia,small LDL particle size-emia, hyper-oxidized LDL-emia, hyper-small denseLDL-emia, hyper-RLP-C-emia, hypo-apoA-I/ApoB ratio-emia,hyper-ApoCIII-emia, dys-ApoE genotype-emia, hyper-lipoprotein (a)-emia,hyper-Lp-PLA2-emia, hyper-CETP activity-emia, hyper-hs-CRP-emia,hypo-EPA-emia (the state wherein EPA value in plasma, serum, erythrocytemembrane, platelet membrane is low), hyper-free fatty acidemia),hyper-fasting glucose-emia, hyper-HbA1c-emia, hyper-HOMA-IR-emia,hyper-intercellular adhesion molecule-1-emia, hyper-IL-6-emia,hyper-PAI-1-emia, hypercreatininemia, hyper-AST-emia, hyper-ALT-emia,hyper-uric acidemia, hyper-8-isoprostane-emia, hyper-TXA2-emia,hyper-LTB2-emia, etc.), therapeutic agent for postprandialhyperglycemia, antiarteriosclerotic agent, platelet aggregationsuppressive agent, therapeutic agent for peripheral circulatoryinsufficiency, agent for preventing onset of cardiovascular events,therapeutic agent for inflammatory diseases (NAFLD, NASH, etc.),anticancer agent, and preventive and therapeutic agents and progressionsuppressant for central diseases (depression, depressive state,obsessive-compulsive disorder, social phobia, panic disorder, etc.).(4-4) A preparation according to any one of the above (4-1) to (4-3)which is administered once a day.(4-5) Method for administering and/or using the preparation according toany one of the above (4-1) to (4-4).(4-6) A method for increasing the ω3PUFA concentration in plasma by oraladministration according to any one of the (4-1) to (4-4).

The fifth aspect of the present invention is a preventive, progressionsuppressing, or therapeutic method for at least one disease selectedfrom the following group.

(5-1) A preventive, progression suppressing, or therapeutic method forat least one disease selected from dyslipidemia (hypercholesterolemia,hyper-LDL cholesterolemia, hyper-non-HDL cholesterolemia, hyper-VLDLcholesterolemia, hypo-HDL cholesterolemia, hypertriglyceridemia,hyper-ApoB-emia, hypo-ApoAI-emia, increased LDL particle number-emia,small LDL particle size-emia, hyper-oxidized LDL-emia, hyper-small denseLDL-emia, hyper-RLP-C-emia, hypo-apoA-I/ApoB ratio-emia,hyper-ApoCIII-emia, dys-ApoE genotype-emia, hyper-lipoprotein (a)-emia,hyper-Lp-PLA2-emia, hyper-CETP activity-emia, hyper-hs-CRP-emia,hypo-EPA-emia (the state wherein EPA value in plasma, serum, erythrocytemembrane, platelet membrane is low), hyper-free fatty acidemia),hyper-fasting glucose-emia, hyper-HbA1c-emia, hyper-HOMA-IR-emia,hyper-intercellular adhesion molecule-1-emia, hyper-IL-6-emia,hyper-PAI-1-emia, hypercreatininemia, hyper-AST-emia, hyper-ALT-emia,hyper-uric acidemia, hyper-8-isoprostane-emia, hyper-TXA2-emia,hyper-LTB2-emia, etc.), postprandial hyperglycemia, arteriosclerosis,increase of platelet aggregation, peripheral circulatory insufficiency,cardiovascular events, inflammatory diseases (NAFLD, NASH, etc.),dementia (Alzheimer-type dementia, vascular dementia, mixed-typedementia, etc.), cancer, and central diseases (depression, depressivestate, obsessive-compulsive disorder, social phobia, panic disorder,etc.), wherein at least one self-emulsifying composition or capsulatedself-emulsifying preparation, drug or veterinary drug selected fromthose according to the above (1-1) to (1-40) and (2-1) to (2-7), isorally administered to a patient.(5-2) A method according to the above (5-1) wherein the self-emulsifyingcomposition or capsulated self-emulsifying preparation, drug orveterinary drug is orally administered in the fasting or before going tobed.(5-3) A method according to the above (5-1) or (5-2) wherein theself-emulsifying composition or capsulated self-emulsifying preparation,drug or veterinary drug is administered once a day.

The sixth aspect of the present invention is the self-emulsifyingcomposition as described below.

(6-1) A self-emulsifying composition wherein the maximum plasma ω3PUFAconcentration determined by orally administering the self-emulsifyingcomposition selected from any one of the above (1-1) to (1-40) and (2-1)to (2-7) at an amount corresponding to 600 mg of the at least onecompound selected from the group consisting of ω3PUFA and theirpharmaceutically acceptable salts and esters to male beagles under thecondition of at least 18 hours of fasting, and conducting the correctionby subtracting plasma ω3PUFA concentration before the administration isat least 50 μg/mL and/or the area under the curve of the plasma ω3PUFAconcentration at 0 to 2 hours after the administration is at least 30μg·hr/mL; the maximum plasma ω3PUFA concentration is at least 50 μg/mLand/or the area under the curve of the plasma ω3PUFA concentration at 0to 2 hours after the administration is at least 50 μg·hr/mL; the maximumplasma ω3PUFA concentration is at least 60 μg/mL and/or the area underthe curve of the plasma ω3PUFA concentration at 0 to 2 hours after theadministration is at least 60 μg·hr/mL; or the maximum plasma ω3PUFAconcentration is at least 70 μg/mL and/or the area under the curve ofthe plasma ω3PUFA concentration at 0 to 2 hours after the administrationis at least 70 μg·hr/mL.(6-2) A self-emulsifying composition wherein the maximum plasma ω3PUFAconcentration determined by orally administering the self-emulsifyingcomposition selected from any one of the above (1-1) to (1-40) and (2-1)to (2-7) at an amount corresponding to 45 mg/kg of body weight of atleast one compound selected from the group consisting of ω3PUFA andtheir pharmaceutically acceptable salts and esters to male cynomolgusmonkeys under the condition of at least 12 hours of fasting, andconducting the correction by subtracting plasma ω3PUFA concentrationbefore the administration is at least 50 μg/mL and/or the area under thecurve of the plasma ω3PUFA concentration at 0 to 12 hours after theadministration is at least 400 μg·hr/mL; or the maximum plasma ω3PUFAconcentration is at least 70 μg/mL and/or the area under the curve ofthe plasma ω3PUFA concentration at 0 to 12 hours after theadministration is at least 500 μg·hr/mL.(6-3) A self-emulsifying composition wherein the maximum plasma ω3PUFAconcentration determined by orally administering the self-emulsifyingcomposition selected from any one of the above (1-1) to (1-40) and (2-1)to (2-7) at an amount corresponding to 1800 mg of at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters to human before the meal, and conducting thecorrection by subtracting plasma ω3PUFA concentration before theadministration is at least 50 μg/mL and/or the area under the curve ofthe plasma ω3PUFA concentration 2 hours after the administration is atleast 10 μg/mL.(6-4) A self-emulsifying composition wherein the maximum plasma ω3PUFAconcentration determined by orally administering the self-emulsifyingcomposition selected from any one of the above (1-1) to (1-40) and (2-1)to (2-7) at an amount corresponding to 1800 mg of at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters to human before the meal, and conducting thecorrection by subtracting plasma ω3PUFA concentration before theadministration is at least 10 μg/mL and/or the area under the curve ofthe plasma ω3PUFA concentration at 0 to 72 hours after theadministration is at least 250 μg·hr/mL.

The seventh aspect of the present invention is the self-emulsifyingcomposition as described below.

(7-1) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or a polyoxyethylenesorbitan fatty acid ester as the emulsifier, which upon administrationto a human satisfies at least one of the following (a) to (e) calculatedby conducting the correction by subtracting the plasma ω3PUFAconcentration before the administration:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours,

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL, and

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 100 μg/mL.

(7-2) A self-emulsifying composition according to the above (7-1)wherein content of the at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters in the composition administered to human is 500 mg to 10000 mg.(7-3) A self-emulsifying composition according to the above (7-1) or(7-2) wherein content of the at least one compound selected from thegroup consisting of ω3PUFA and their pharmaceutically acceptable saltsand esters in the composition administered to human is at least one of500 mg, 1000 mg, 1800 mg, 2000 mg, 3600 mg, 4000 mg, 6000 mg, and 8000mg.(7-4) A self-emulsifying composition according to any one of the above(7-1) to (7-3) wherein content of the at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters in the composition administered to human isselected from 1800 mg, 2000 mg, 3600 mg, and 4000 mg.(7-5) A self-emulsifying composition according to any one of the above(7-1) to (7-4) wherein the ω3PUFA and their pharmaceutically acceptablesalts and esters in the composition administered to human are at leastone compound selected from the group consisting of EPA and itspharmaceutically acceptable salts and esters.(7-6) A self-emulsifying composition according to the above (7-5)wherein the EPA and its pharmaceutically acceptable salts and esters areethyl ester of EPA.(7-7) A self-emulsifying composition according to any one of the above(7-1) to (7-6) wherein, when the composition is administered, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL, and the area under the curve of theplasma ω3PUFA concentration at 0 to 72 hours after the administration isat least 500 μg·hr/mL.(7-8) A self-emulsifying composition according to any one of the above(7-1) to (7-7) wherein, when the composition is administered, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL, and the plasma ω3PUFA concentration24 hours after the administration is 5 to 100 μg/mL.(7-9) A self-emulsifying composition according to any one of the above(7-1) to (7-8) wherein, when the composition is administered, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL, and the time required to reach themaximum plasma ω3PUFA concentration (Tmax) is up to 6 hours.(7-10) A self-emulsifying composition according to any one of the above(7-1) to (7-9) wherein, when the composition is administered, the areaunder the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration calculated by conducting the correction bysubtracting the plasma ω3PUFA concentration before the administration isat least 500 μg·hr/mL, and the time required to reach the maximum plasmaω3PUFA concentration (Tmax) is up to 6 hours.(7-11) A self-emulsifying composition according to any one of the above(7-1) to (7-10) wherein, when the composition is administered underfasting, the maximum plasma ω3PUFA concentration calculated byconducting the correction by subtracting the plasma ω3PUFA concentrationbefore the administration is at three times as high as the maximumplasma ω3PUFA concentration immediately after the meal, or the areaunder the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration is at least twice as large as the area underthe curve of the plasma ω3PUFA concentration immediately after the meal.(7-12) A self-emulsifying composition according to any one of the above(7-1) to (7-11) wherein the composition contains lecithin and apolyoxyethylene sorbitan fatty acid ester as the emulsifier.(7-13) A self-emulsifying composition according to any one of the above(7-1) to (7-12) wherein the composition further contains polyoxyethylenecastor oil as the emulsifier.(7-14) A self-emulsifying composition according to any one of (7-1) to(7-13) wherein content of the emulsifier is 1 to 29% by weight when thetotal amount of the self-emulsifying composition is 100% by weight.(7-15) A self-emulsifying composition according to any one of (7-1) to(7-14) wherein content of the lecithin is 3 to 40 parts by weight or 1to 25 parts by weight in relation to 100 parts by weight of the at leastone compound selected from the group consisting of ω3PUFA and theirpharmaceutically acceptable salts and esters.(7-16) A self-emulsifying composition according to any one of the above(7-1) to (7-15) wherein content of the polyoxyethylene castor oil is upto 120 parts by weight in relation to 100 parts by weight of thepolyoxyethylene sorbitan fatty acid ester in the composition.(7-17) A self-emulsifying composition according to any one of the above(7-1) to (7-14) wherein the composition is at least one member selectedfrom the group consisting of therapeutic agent for dyslipidemia(hypercholesterolemia, hyper-LDL cholesterolemia, hyper-non-HDLcholesterolemia, hyper-VLDL cholesterolemia, hypo-HDL cholesterolemia,hypertriglyceridemia, hyper-ApoB-emia, hypo-ApoAI-emia, increased LDLparticle number-emia, small LDL particle size-emia, hyper-oxidizedLDL-emia, hyper-small dense LDL-emia, hyper-RLP-C-emia, hypo-apoA-I/ApoBratio-emia, hyper-ApoCIII-emia, dys-ApoE genotype-emia,hyper-lipoprotein (a)-emia, hyper-Lp-PLA2-emia, hyper-CETPactivity-emia, hyper-hs-CRP-emia, hypo-EPA-emia (the state wherein EPAvalue in plasma, serum, erythrocyte membrane, platelet membrane is low),hyper-free fatty acidemia), hyper-fasting glucose-emia,hyper-HbA1c-emia, hyper-HOMA-IR-emia, hyper-intercellular adhesionmolecule-1-emia, hyper-IL-6-emia, hyper-PAI-1-emia, hypercreatininemia,hyper-AST-emia, hyper-ALT-emia, hyper-uric acidemia,hyper-8-isoprostane-emia, hyper-TXA2-emia, hyper-LTB2-emia, etc.),therapeutic agent for postprandial hyperglycemia, antiarterioscleroticagent, platelet aggregation suppressive agent, therapeutic agent forperipheral circulatory insufficiency, agent for preventing onset ofcardiovascular events, therapeutic agent for inflammatory diseases(NAFLD, NASH, etc.), anticancer agent, and preventive and therapeuticagents and progression suppressant for central diseases (depression,depressive state, obsessive-compulsive disorder, social phobia, panicdisorder, etc.).(7-18) A self-emulsifying composition according to any one of the above(7-1) to (7-17) wherein the composition containing 500 mg to 10000 mg ofat least one compound selected from the group consisting of ω3PUFA andtheir pharmaceutically acceptable salts and esters is administered oncea day.(7-19) A self-emulsifying composition according to any one of the above(7-1) to (7-18) wherein the composition is administered under fasting,before the meal, immediately after the meal, or after the meal.(7-20) A self-emulsifying composition according to any one of the above(7-1) to (7-19) comprising at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters, lecithin, and a polyoxyethylene sorbitan fatty acid ester andpolyoxyethylene castor oil as emulsifiers, wherein content of thepolyoxyethylene castor oil is up to 120 parts by weight in relation to100 parts by weight of the polyoxyethylene sorbitan fatty acid ester inthe composition, and wherein, when the composition is administered to ahuman at an amount in terms of the at least one compound selected fromthe group consisting of ω3PUFA and their pharmaceutically acceptablesalts and esters of 500 mg to 10000 mg, the maximum plasma ω3PUFAconcentration calculated by correcting the value by subtracting theplasma ω3PUFA concentration before the administration is at least 50μg/mL, and the area under the curve of the plasma ω3PUFA concentrationat 0 to 72 hours after the administration is at least 500 μg·hr/mL.(7-21) A self-emulsifying composition according to any one of (7-1) to(7-20) wherein content of the at least one compound selected from thegroup consisting of ω3PUFA and their pharmaceutically acceptable saltsand esters is 70 to 90%) by weight when total amount of theself-emulsifying composition is 100% by weight.(7-22) A self-emulsifying composition according to any one of (7-1) to(7-21) wherein content of the at least one compound selected from thegroup consisting of EPA and its pharmaceutically acceptable salts andesters is 70 to 90% by weight when total amount of the self-emulsifyingcomposition is 100% by weight.(7-23) A self-emulsifying composition according to any one of (7-1) to(7-22) wherein content of the lecithin is 3 to 40 parts by weight or 1to 25 parts by weight in relation to 100 parts by weight of the at leastone compound selected from the group consisting of ω3PUFA and theirpharmaceutically acceptable salts and esters.(7-24) A self-emulsifying composition according to any one of the above(7-1) to (7-23) wherein the composition contains water.(7-25) A self-emulsifying composition according to any one of the above(7-1) to (7-24) wherein content of the water in the composition is 0.5to 6% by weight of the total weight of the composition.(7-26) A self-emulsifying composition according to any one of the above(7-1) to (7-25) wherein content of the ethanol in the composition is upto 4% by weight of the total weight of the composition.

f) the polyhydric alcohol is up to 4% by weight of the total weight ofthe composition.

(7-27) A self-emulsifying composition according to any one of the above(7-1) to (7-26) comprising, when total amount of the composition is 100%by weight,

a) 70 to 90% by weight of EPA-E,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of a polyoxyethylene sorbitan fatty acid ester asthe emulsifier, and

d) 3 to 40 parts by weight, or 1 to 25 parts by weight of lecithin inrelation to 100 parts by weight of the lecithin, wherein

e) the ethanol and/or the polyhydric alcohol is up to 4% by weight ofthe total amount of the composition.

(7-28) A self-emulsifying composition according to any one of the above(7-1) to (7-27) wherein the composition is orally administered.(7-29) A self-emulsifying composition according to any one of the above(7-1) to (7-28) wherein the composition is a composition for oraladministration.(7-30) A self-emulsifying composition according to any one of the above(7-1) to (7-29) wherein the composition is a capsule.(7-31) A method for administrating at least one self-emulsifyingcomposition selected from any one of the above (7-1) to (7-30) to humanor a method for using such composition in human.(7-32) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters, lecithin, or an emulsifier which, whenadministered to human, satisfies at least one of the (a) to (i)calculated by conducting the correction by subtracting the plasma ω3PUFAconcentration before the administration:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours,

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL,

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 100 μg/mL,

(f) the area under the curve of the plasma ω3PUFA concentration at 0 to24 hours after the administration is at least 100 μg·hr/mL,

(g) the maximum plasma ω3PUFA concentration in steady state is at least50 μg/mL,

(h) the minimum plasma ω3PUFA concentration in steady state is at least10 μg/mL, and

(i) the average ω3PUFA plasma concentration in steady state is at least30 μg/mL.

(7-33) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or an emulsifier,which, when administered to human, satisfies at least one of the (a) to(i) calculated by conducting the correction by subtracting the plasmaω3PUFA concentration before the administration:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours,

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL,

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 100 μg/mL,

(f) the area under the curve of the plasma ω3PUFA concentration at 0 to24 hours after the administration is at least 100 μg·hr/mL,

(g) the maximum plasma ω3PUFA concentration in steady state is at least50 μg/mL,

(h) the minimum plasma ω3PUFA concentration in steady state is at least10 μg/mL, and

(i) the average ω3PUFA plasma concentration in steady state is at least30 μg/mL.

(7-34) A self-emulsifying composition according to the above (7-33)wherein the emulsifier is at least one member selected from cationicsurfactants, anionic surfactants, amphoteric surfactants, and nonionicsurfactants.(7-35) A self-emulsifying composition according to the above (7-33) or(7-34) wherein the emulsifier or the nonionic surfactant is apolyoxyethylene sorbitan fatty acid ester.(7-36) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or a polyoxyethylenesorbitan fatty acid ester as an emulsifier, which, when administered tohuman, satisfies at least one of the (a) to (i) calculated by conductingthe correction by subtracting the plasma ω3PUFA concentration before theadministration:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours,

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL,

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 100 μg/mL,

(f) the area under the curve of the plasma ω3PUFA concentration at 0 to24 hours after the administration is at least 100 μg·hr/mL,

(g) the maximum plasma ω3PUFA concentration in steady state is at least50 μg/mL,

(h) the minimum plasma ω3PUFA concentration in steady state is at least10 μg/mL, and

(i) the average ω3PUFA plasma concentration in steady state is at least30 μg/mL.

(7-37) A self-emulsifying composition according to any one of the above(7-33) to (7-36) wherein content of the at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters contained in the composition to beadministered to human is 500 mg to 10000 mg.(7-38) A self-emulsifying composition according to any one of the above(7-33) to (7-37) wherein content of the at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters contained in the composition to beadministered to human is at least one amount selected from 500 mg, 1000mg, 1800 mg, 2000 mg, 3600 mg, 4000 mg, 6000 mg, and 8000 mg.(7-39) A self-emulsifying composition according to any one of the above(7-33) to (7-38) wherein content of the at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters contained in the composition to beadministered to human is at least one amount selected from 1800 mg, 2000mg, 3600 mg, and 4000 mg.(7-40) A self-emulsifying composition according to any one of the above(7-33) to (7-39) wherein the ω3PUFA and their pharmaceuticallyacceptable salts and esters contained in the composition to beadministered to human are at least one member selected from the groupconsisting of EPA and its pharmaceutically acceptable salts and esters.(7-41) A self-emulsifying composition according to the above (7-40)wherein the EPA and its pharmaceutically acceptable salts and esters areethyl ester of EPA.(7-42) A self-emulsifying composition according to any one of the above(7-33) to (7-41) wherein, upon administration of the composition, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL and the area under the curve of theplasma ω3PUFA concentration at 0 to 72 hours after the administration isat least 500 μg·hr/mL.(7-43) A self-emulsifying composition according to any one of the above(7-33) to (7-42) wherein, upon administration of the composition, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL and the plasma ω3PUFA concentration24 hours after the administration is 5 to 100 μg/mL.(7-44) A self-emulsifying composition according to any one of the above(7-33) to (7-43) wherein, upon administration of the composition, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL and the time required to reach themaximum plasma ω3PUFA concentration (Tmax) is up to 6 hours.(7-45) A self-emulsifying composition according to any one of the above(7-33) to (7-44) wherein, upon administration of the composition, thearea under the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration calculated by conducting the correction bysubtracting the plasma ω3PUFA concentration before the administration isat least 500 μg·hr/mL, and the time required to reach the maximum plasmaω3PUFA concentration (Tmax) is up to 6 hours.(7-46) A self-emulsifying composition according to any one of the above(7-33) to (7-45) wherein, upon administration of the composition, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least 50 μg/mL and the average ω3PUFA plasmaconcentration in steady state is at least 30 μg/mL.(7-47) A self-emulsifying composition according to any one of the above(7-33) to (7-46) wherein, upon administration of the composition, themaximum plasma ω3PUFA concentration calculated by conducting thecorrection by subtracting the plasma ω3PUFA concentration before theadministration is at least three times as high as the maximum plasmaω3PUFA concentration immediately after the meal, or the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration is at least twice as large as the area under the curve ofthe plasma ω3PUFA concentration immediately after the meal.(7-48) A self-emulsifying composition according to any one of the above(7-33) to (7-47) wherein the composition contains lecithin and anemulsifier.(7-49) A self-emulsifying composition according to any one of the above(7-33) to (7-48) wherein the composition contains lecithin and anonionic surfactant as the emulsifier.(7-50) A self-emulsifying composition according to any one of the above(7-33) to (7-49) wherein the composition contains lecithin and apolyoxyethylene sorbitan fatty acid ester as the emulsifier.(7-51) A self-emulsifying composition according to any one of the above(7-33) to (7-50) wherein the composition contains lecithin and apolyoxyethylene sorbitan fatty acid ester as a nonionic surfactant.(7-52) A self-emulsifying composition according to any one of the above(7-33) to (7-51) wherein the composition further containspolyoxyethylene castor oil as the emulsifier.(7-53) A self-emulsifying composition according to any one of the above(7-33) to (7-52) wherein content of the emulsifier is 1 to 29% by weightwhen total amount of the self-emulsifying composition is 100% by weight.(7-54) A self-emulsifying composition according to any one of the above(7-33) to (7-53) wherein content of the polyoxyethylene castor oil is upto 120 parts by weight in relation to 100 parts by weight of thepolyoxyethylene sorbitan fatty acid ester in the composition.(7-55) A self-emulsifying composition according to any one of the above(7-33) to (7-54) wherein the composition is at least one member selectedfrom the group consisting of therapeutic agent for dyslipidemia(hypercholesterolemia, hyper-LDL cholesterolemia, hyper-non-HDLcholesterolemia, hyper-VLDL cholesterolemia, hypo-HDL cholesterolemia,hypertriglyceridemia, hyper-ApoB-emia, hypo-ApoAI-emia, increased LDLparticle number-emia, small LDL particle size-emia, hyper-oxidizedLDL-emia, hyper-small dense LDL-emia, hyper-RLP-C-emia, hypo-apoA-I/ApoBratio-emia, hyper-ApoCIII-emia, dys-ApoE genotype-emia,hyper-lipoprotein (a)-emia, hyper-Lp-PLA2-emia, hyper-CETPactivity-emia, hyper-hs-CRP-emia, hypo-EPA-emia (the state wherein EPAvalue in plasma, serum, erythrocyte membrane, platelet membrane is low),hyper-free fatty acidemia), hyper-fasting glucose-emia,hyper-HbA1c-emia, hyper-HOMA-IR-emia, hyper-intercellular adhesionmolecule-1-emia, hyper-IL-6-emia, hyper-PAI-1-emia, hypercreatininemia,hyper-AST-emia, hyper-ALT-emia, hyper-uric acidemia,hyper-8-isoprostane-emia, hyper-TXA2-emia, hyper-LTB2-emia, etc.),therapeutic agent for postprandial hyperglycemia, antiarterioscleroticagent, platelet aggregation suppressive agent, therapeutic agent forperipheral circulatory insufficiency, agent for preventing onset ofcardiovascular events, therapeutic agent for inflammatory diseases(NAFLD, NASH, etc.), anticancer agent, and preventive and therapeuticagents and progression suppressant for central diseases (depression,depressive state, obsessive-compulsive disorder, social phobia, panicdisorder, etc.).(7-56) A self-emulsifying composition according to any one of the above(7-33) to (7-55) wherein the composition containing at least onecompound selected from the group consisting of ω3PUFA and theirpharmaceutically acceptable salts and esters at an amount of 500 mg to10000 mg is administered once a day.(7-57) A self-emulsifying composition according to any one of the above(7-33) to (7-56) comprising at least one compound selected from thegroup consisting of ω3PUFA and their pharmaceutically acceptable saltsand esters, lecithin, and a polyoxyethylene sorbitan fatty acid esterand polyoxyethylene castor oil as emulsifiers wherein content of thepolyoxyethylene castor oil is up to 120 parts by weight in relation to100 parts by weight of the polyoxyethylene sorbitan fatty acid ester inthe composition, and wherein, when the composition is administered tohuman at an amount in terms of the at least one compound selected fromthe group consisting of ω3PUFA and their pharmaceutically acceptablesalts and esters of 500 mg to 10000 mg, the maximum plasma ω3PUFAconcentration calculated by conducting the correction by subtractingplasma ω3PUFA concentration before the administration is at least 50μg/mL and the area under the curve of the plasma ω3PUFA concentration at0 to 72 hours after the administration is at least 500 μg·hr/mL.(7-58) A self-emulsifying composition according to any one of the above(7-33) to (7-57) wherein content of the at least one compound selectedfrom the group consisting of 03PUFA and their pharmaceuticallyacceptable salts and esters is 70 to 90% by weight when total amount ofthe self-emulsifying composition is 100% by weight.(7-59) A self-emulsifying composition according to any one of the above(7-33) to (7-58) wherein content of the at least one compound selectedfrom the group consisting of EPA and its pharmaceutically acceptablesalts and esters is 70 to 90% by weight when total amount of theself-emulsifying composition is 100% by weight.(7-60) A self-emulsifying composition according to any one of the above(7-33) to (7-59) wherein content of the lecithin is 3 to 40 parts byweight or 1 to 25 parts by weight in relation to 100 parts by weight ofthe at least one compound selected from the group consisting of ω3PUFAand their pharmaceutically acceptable salts and esters.(7-61) A self-emulsifying composition according to any one of the above(7-33) to (7-60) wherein the composition contains water.(7-62) A self-emulsifying composition according to any one of the above(7-33) to (7-61) wherein content of the ethanol in the composition is upto 4% by weight of the total weight of the composition.

f) the polyhydric alcohol is up to 4% by weight in the total weight ofthe composition.

(7-63) A self-emulsifying composition according to any one of the above(7-33) to (7-62) wherein content of water in the composition is 0.5 to6% by weight of the total weight of the composition.(7-64) A self-emulsifying composition according to any one of the above(7-33) to (7-63) comprising, when the total composition is 100% byweight,

a) 70 to 90% by weight of EPA-E,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of a polyoxyethylene sorbitan fatty acid ester asthe emulsifier, and

d) 3 to 40 parts by weight or 1 to 25 parts by weight of lecithin inrelation to 100 parts by weight of the EPA-E, wherein

e) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe total composition.

(7-65) A self-emulsifying composition according to any one of the above(7-33) to (7-64) comprising, when the total composition is 100% byweight,

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of a polyoxyethylene sorbitan fatty acid ester andpolyoxyethylene castor oil as emulsifiers, and

d) 1 to 25 parts by weight of lecithin in relation to 100 parts byweight of the at least one compound selected from the group consistingof ω3PUFA and their pharmaceutically acceptable salts and esters,wherein

e) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe total amount of the composition, and

f) content of polyoxyethylene castor oil is up to 120 parts by weight inrelation to 100 parts by weight of the polyoxyethylene sorbitan fattyacid ester in the composition;

the composition satisfying at least one of the (a) to (i) as describedbelow calculated by conducting the correction by subtracting ω3PUFAconcentration in plasma before the administration, when theself-emulsifying composition is administered once a day at an amount interms of the at least one compound selected from the group consisting ofω3PUFA and their pharmaceutically acceptable salts and esters of oneselected from 1800 mg, 2000 mg, 3600 mg, and 4000 mg:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours,

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL,

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 100 μg/mL,

(f) the area under the curve of the plasma ω3PUFA concentration at 0 to24 hours after the administration is at least 100 μg·hr/mL,

(g) the maximum plasma ω3PUFA concentration in steady state is at least50 μg/mL,

(h) the minimum plasma ω3PUFA concentration in steady state is at least10 μg/mL, and

(i) the average ω3PUFA plasma concentration in steady state is at least30 μg/mL.

(7-66) A self-emulsifying composition according to the above (7-65)wherein the at least one compound selected from the group consisting ofω3PUFA and their pharmaceutically acceptable salts and esters is theEPA-E.(7-67) A self-emulsifying composition according to any one of the above(6-1) to (7-66) which is substantially free from at least one compoundselected from the group consisting of DHA and its pharmaceuticallyacceptable salts and esters.(7-68) A self-emulsifying composition according to any one of the above(7-1) to (7-67) wherein content of the at least one compound selectedfrom the group consisting of DHA and its pharmaceutically acceptablesalts and esters is up to 1% by weight of the total amount of thecomposition.(7-69) A method for administering at least one self-emulsifyingcomposition selected from the above (7-33) to (7-68) to human or usingsuch composition in human.(7-70) A method for administering a self-emulsifying compositioncomprising at least one compound selected from the group consisting ofω3PUFA and their pharmaceutically acceptable salts and esters as well aslecithin and/or a polyoxyethylene sorbitan fatty acid ester as theemulsifier, wherein the method satisfies at least one of the (a) to (i)as described below calculated by conducting the correction bysubtracting ω3PUFA concentration in plasma before the administration,when the self-emulsifying composition is administered to human:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours, and

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL,

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 500 μg/mL,

(f) the area under the curve of the plasma ω3PUFA concentration at 0 to24 hours after the administration is at least 100 μg·hr/mL,

(g) the maximum plasma ω3PUFA concentration in steady state is at least50 μg/mL,

(h) the minimum plasma ω3PUFA concentration in steady state is at least10 μg/mL, and

(i) the average ω3PUFA plasma concentration in steady state is at least30 μg/mL.

(7-71) A method for administering the self-emulsifying compositionaccording to any one of the above (7-33) to (7-67) comprising, when thetotal composition is 100% by weight,

a) 70 to 90% by weight of at least one compound selected from the groupconsisting of ω3PUFA and their pharmaceutically acceptable salts andesters,

b) 0.5 to 6% by weight of water,

c) 1 to 29% by weight of a polyoxyethylene sorbitan fatty acid ester asthe emulsifier, and

d) 3 to 40 parts by weight or 1 to 25 parts by weight of lecithin inrelation to 100 parts by weight of the at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters, wherein

e) content of ethanol and/or polyhydric alcohol is up to 4% by weight ofthe total composition,

the method satisfying at least one of the (a) to (i) as described belowcalculated by conducting the correction by subtracting ω3PUFAconcentration in plasma before the administration, when theself-emulsifying composition is administered once a day at an amount interms of the at least one compound selected from the group consisting ofω3PUFA and their pharmaceutically acceptable salts and esters of oneselected from 1800 mg, 2000 mg, 3600 mg, and 4000 mg:

(a) the maximum plasma ω3PUFA concentration is at least 50 μg/mL,

(b) the plasma ω3PUFA concentration 2 hours after the administration isat least 20 μg/mL,

(c) the time required to reach the maximum plasma ω3PUFA concentration(Tmax) is up to 6 hours,

(d) the area under the curve of the plasma ω3PUFA concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL,

(e) the plasma ω3PUFA concentration 24 hours after the administration is5 to 100 μg/mL,

(f) the area under the curve of the plasma ω3PUFA concentration at 0 to24 hours after the administration is at least 100 μg·hr/mL,

(g) the maximum plasma ω3PUFA concentration in steady state is at least50 μg/mL,

(h) the minimum plasma ω3PUFA concentration in steady state is at least10 μg/mL, and

(i) the average ω3PUFA plasma concentration in steady state is at least30 μg/mL.

The eighth aspect of the present invention is the self-emulsifyingcomposition as described below.

(8-1) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or a polyoxyethylenesorbitan fatty acid ester as the emulsifier, wherein when theself-emulsifying composition is administered at an amount in terms ofω3PUFA of 500 to 2500 mg (for example, 1800 mg, 2000 mg) to eachindividual, at least one member selected from the maximum plasma ω3PUFAconcentration calculated by correcting the value by subtracting theplasma ω3PUFA concentration before the administration, the plasma ω3PUFAconcentration 2 hours after the administration, the time required toreach the maximum plasma ω3PUFA concentration, and the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration is substantially the same as the corresponding valueobtained by administering 1800 mg/day of the ω3PUFA immediately afterthe meal.(8-2) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or a polyoxyethylenesorbitan fatty acid ester as the emulsifier, wherein when theself-emulsifying composition is administered at an amount in terms ofω3PUFA of 500 to 2500 mg (for example, 1800 mg, 2000 mg) to eachindividual, at least one value selected from the maximum plasma ω3PUFAconcentration calculated by correcting the value by subtracting theplasma ω3PUFA concentration before the administration, the plasma ω3PUFAconcentration 2 hours after the administration, the time required toreach the maximum plasma ω3PUFA concentration, and the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration is 70 to 130% of the corresponding value obtained byadministering 1800 mg/day of the ω3PUFA (for example, Epadel containingthe EPA-E) immediately after the meal.(8-3) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or an emulsifier,wherein when the self-emulsifying composition is administered at anamount in terms of ω3PUFA of 500 to 2500 mg to each individual, at leastone member selected from the maximum plasma ω3PUFA concentrationcalculated by correcting the value by subtracting the plasma ω3PUFAconcentration before the administration, the plasma ω3PUFA concentration2 hours after the administration, the time required to reach the maximumplasma ω3PUFA concentration, the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration, the areaunder the curve of the plasma ω3PUFA concentration at 0 to 24 hoursafter the administration, maximum ω3PUFA plasma concentration in steadystate, minimum ω3PUFA plasma concentration in steady state, and averageω3PUFA plasma concentration in steady state is substantially the same asthe corresponding value obtained by administering 1800 mg/day of theω3PUFA immediately after the meal.(8-4) A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or an emulsifier,wherein when the self-emulsifying composition is administered at anamount in terms of ω3PUFA of 500 to 10000 mg to each individual, atleast one value selected from the maximum plasma ω3PUFA concentrationcalculated by correcting the value by subtracting the plasma ω3PUFAconcentration before the administration, the plasma ω3PUFA concentration2 hours after the administration, the time required to reach the maximumplasma ω3PUFA concentration, the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration, the areaunder the curve of the plasma ω3PUFA concentration at 0 to 24 hoursafter the administration, maximum ω3PUFA plasma concentration in steadystate, minimum ω3PUFA plasma concentration in steady state, and averageω3PUFA plasma concentration in steady state is 70 to 130% of thecorresponding value obtained by administering 1800 mg/day of the ω3PUFA(for example, Epadel containing the EPA-E) immediately after the meal.(8-5) A self-emulsifying composition according to the above (8-3) or(8-4) wherein the emulsifier is at least one member selected fromcationic surfactant, anionic surfactant, amphoteric surfactant, andnonionic surfactant.(8-6) A self-emulsifying composition according to the above (8-5)wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acidester.(8-7) A self-emulsifying composition according to any one of the above(8-1) to (8-6) wherein the maximum plasma ω3PUFA concentration is atleast 50 μg/mL.(8-8) A self-emulsifying composition according to any one of the above(8-1) to (8-7) wherein the plasma ω3PUFA concentration 2 hours after theadministration is at least 20 μg/mL.(8-9) A self-emulsifying composition according to any one of the above(8-1) to (8-8) wherein the time required to reach the maximum plasmaω3PUFA concentration is up to 6 hours.(8-10) A self-emulsifying composition according to any one of the above(8-1) to (8-9) wherein the area under the curve of the plasma ω3PUFAconcentration at 0 to 72 hours after the administration is at least 500μg·hr/mL.(8-11) A self-emulsifying composition according to any one of the above(8-3) to (8-10) wherein the area under the curve of the plasma ω3PUFAconcentration at 0 to 24 hours after the administration is at least 100μg·hr/mL.(8-12) A self-emulsifying composition according to any one of the above(8-3) to (8-11) wherein the maximum plasma ω3PUFA concentration insteady state is at least 50 μg·hr/mL.(8-13) A self-emulsifying composition according to any one of the above(8-3) to (8-12) wherein the minimum plasma ω3PUFA concentration insteady state is at least 10 μg·hr/mL.(8-14) A self-emulsifying composition according to any one of the above(8-3) to (8-13) wherein the average ω3PUFA plasma concentration insteady state is at least 30 μg·hr/mL.(8-15) A self-emulsifying composition according to any one of the above(8-1) to (8-14) wherein the ω3PUFA and their pharmaceutically acceptablesalts and esters administered are at least one member selected from thegroup consisting of EPA and its pharmaceutically acceptable salts andesters.(8-16) A self-emulsifying composition according to any one of the above(8-1) to (8-15) wherein content of the at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters is 70 to 90% by weight when total amount ofthe self-emulsifying composition is 100% by weight.(8-17) A self-emulsifying composition according to the above (8-15)wherein the EPA and its pharmaceutically acceptable salts and esters areethyl ester of EPA.(8-18) A self-emulsifying composition according to any one of the above(8-1) to (8-17) wherein content of the at least one compound selectedfrom the group consisting of EPA and its pharmaceutically acceptablesalts and esters is 70 to 90% by weight when total amount of theself-emulsifying composition is 100% by weight.(8-19) A self-emulsifying composition according to any one of the above(8-1) to (8-18) wherein the composition contains lecithin and a nonionicsurfactant as the emulsifier.(8-20) A self-emulsifying composition according to any one of the above(8-1) to (8-19) wherein the composition contains lecithin and apolyoxyethylene sorbitan fatty acid ester as the emulsifier.(8-21) A self-emulsifying composition according to any one of the above(8-1) to (8-20) wherein the composition contains lecithin and apolyoxyethylene sorbitan fatty acid ester as a nonionic surfactant.(8-22) A self-emulsifying composition according to any one of the above(8-1) to (8-21) wherein the composition further contains polyoxyethylenecastor oil as the emulsifier.(8-23) A self-emulsifying composition according to any one of the above(8-1) to (8-22) wherein content of the emulsifier is 1 to 29% by weightwhen total amount of the self-emulsifying composition is 100% by weight.(8-24) A self-emulsifying composition according to any one of the above(8-1) to (8-23) wherein content of the polyoxyethylene castor oil is upto 120 parts by weight in relation to 100 parts by weight of thepolyoxyethylene sorbitan fatty acid ester in the composition.(8-25) A self-emulsifying composition according to any one of the above(8-1) to (8-24) wherein the composition is administered once a day.(8-26) A self-emulsifying composition according to any one of the above(8-1) to (8-25) wherein the composition is administered under fasting,before the meal, immediately after the meal, or after the meal.(8-27) A self-emulsifying composition according to any one of the above(8-1) to (8-26) comprising EPA-E, lecithin, and a polyoxyethylenesorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers,wherein, when the self-emulsifying composition is administered at anamount in terms of the ω3PUFA of 1800 mg of 2000 mg to each individualonce a day under fasting, at least one member selected from the maximumplasma ω3PUFA concentration calculated by correcting the value bysubtracting the plasma ω3PUFA concentration before the administration,the plasma ω3PUFA concentration 2 hours after the administration, thetime required to reach the maximum plasma ω3PUFA concentration, and thearea under the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration is substantially the same as the correspondingvalue obtained when the self-emulsifying composition is administered ata daily dose in terms of the ω3PUFA of 1800 mg immediately after themeal.(8-28) A self-emulsifying composition according to any one of the above(8-1) to (8-27) comprising EPA-E, lecithin, and a polyoxyethylenesorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers,wherein, when the self-emulsifying composition is administered at anamount in terms of the ω3PUFA of 1800 mg or 2000 mg to each individualonce a day under fasting, at least one member selected from the maximumplasma ω3PUFA concentration calculated by correcting the value bysubtracting the plasma ω3PUFA concentration before the administration,the plasma ω3PUFA concentration 2 hours after the administration, thetime required to reach the maximum plasma ω3PUFA concentration, and thearea under the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration is 70 to 130% of the corresponding valueobtained when the self-emulsifying composition is administered at adaily dose in terms of the ω3PUFA of 1800 mg immediately after the meal.(8-29) A self-emulsifying composition according to any one of the above(8-1) to (8-28) comprising EPA-E, lecithin, and a polyoxyethylenesorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers,wherein, when the self-emulsifying composition is administered at anamount in terms of the ω3PUFA of 500 mg to 1500 mg to each individualonce a day under fasting, at least one member selected from the maximumplasma ω3PUFA concentration calculated by correcting the value bysubtracting the plasma ω3PUFA concentration before the administration,the plasma ω3PUFA concentration 2 hours after the administration, thetime required to reach the maximum plasma ω3PUFA concentration, and thearea under the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration is substantially the same as the correspondingvalue obtained when the self-emulsifying composition is administered ata daily dose in terms of the ω3PUFA of 1800 mg immediately after themeal.(8-30) A self-emulsifying composition according to any one of the above(8-1) to (8-29) comprising EPA-E, lecithin, and a polyoxyethylenesorbitan fatty acid ester and polyoxyethylene castor oil as emulsifiers,wherein, when the self-emulsifying composition is administered at anamount in terms of the ω3PUFA of 500 to 1500 mg to each individual oncea day under fasting, at least one value selected from the maximum plasmaω3PUFA concentration calculated by correcting the value by subtractingthe plasma ω3PUFA concentration before the administration, the plasmaω3PUFA concentration 2 hours after the administration, the time requiredto reach the maximum plasma ω3PUFA concentration, and the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration is 70 to 130% of the corresponding value obtained whenthe self-emulsifying composition is administered at a daily dose interms of the ω3PUFA of 1800 mg immediately after the meal.

The ninth aspect of the present invention is the method as describedbelow.

(9-1) A method for increasing the blood ω3PUFA concentration wherein atleast one compound selected from the group consisting of ω3PUFA andtheir pharmaceutically acceptable salts and esters is administered incombination with lecithin.(9-2) A method for increasing the blood concentration according to theabove (9-1) wherein the ω3PUFA is administered at least 500 mg/day.(9-3) A method for increasing the blood concentration according to theabove (9-1) or (9-2) wherein polyoxyethylene sorbitan fatty acid esteris administered in combination.(9-4) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-3) wherein polyoxyethylene castor oil isadministered in combination.(9-5) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-4) wherein the emulsifier is administeredin combination at an amount of 5 to 45 parts by weight in relation to100 parts by weight of the ω3PUFA.(9-6) A method for increasing the blood concentration according to theabove (9-4) or (9-5) wherein the polyoxyethylene castor oil isadministered at an amount of up to 120 parts by weight in relation to100 parts by weight of polyoxyethylene sorbitan fatty acid ester.(9-7) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-6) wherein the lecithin is administered incombination at an amount of 1 to 25 parts by weight in relation to 100parts by weight of the ω3PUFA.(9-8) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-7) wherein the ω3PUFA is administered onceday.(9-9) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-8) wherein the ω3PUFA is administered underfasting, before the meal, immediately after the meal, or after the meal.(9-10) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-9) wherein, when the composition isadministered at an amount in terms of the ω3PUFA of 500 to 10000 mg (forexample, 1800 mg, 2000 mg) to each individual once a day under fasting,before the meal, immediately after the meal, or after the meal, at leastone member selected from the maximum plasma ω3PUFA concentrationcalculated by correcting the value by subtracting the plasma ω3PUFAconcentration before the administration, the plasma ω3PUFA concentration2 hours after the administration, the time required to reach the maximumplasma ω3PUFA concentration, and the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration issubstantially the same as the corresponding value obtained byadministering 1800 mg/day of the ω3PUFA immediately after the meal.(9-11) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-10) wherein, when the composition isadministered at an amount in terms of the ω3PUFA of 500 to 10000 mg (forexample, 1800 mg, 2000 mg) to each individual once a day under fasting,before the meal, immediately after the meal, or after the meal, at leastone value selected from the maximum plasma ω3PUFA concentrationcalculated by correcting the value by subtracting the plasma ω3PUFAconcentration before the administration, the plasma ω3PUFA concentration2 hours after the administration, the time required to reach the maximumplasma ω3PUFA concentration, and the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration is 70 to130% of the corresponding value obtained by administering 1800 mg/day ofthe ω3PUFA (for example, Epadel containing the EPA-E) immediately afterthe meal.(9-12) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-9) wherein, when the composition isadministered at an amount in terms of the ω3PUFA of 500 to 10000 mg (forexample, 1800 mg, 2000 mg) to each individual once a day under fasting,before the meal, immediately after the meal, or after the meal, at leastone value selected from the maximum plasma ω3PUFA concentrationcalculated by correcting the value by subtracting the plasma ω3PUFAconcentration before the administration, the plasma ω3PUFA concentration2 hours after the administration, the time required to reach the maximumplasma ω3PUFA concentration, the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration, the areaunder the curve of the plasma ω3PUFA concentration at 0 to 24 hoursafter the administration, maximum plasma concentration in steady state,minimum plasma concentration in steady state, and average plasmaconcentration in steady state is substantially the same as thecorresponding value obtained by administering 1800 mg/day of the ω3PUFAimmediately after the meal.(9-13) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-9) wherein, when the composition isadministered at an amount in terms of the ω3PUFA of 500 to 10000 mg (forexample, 1800 mg, 2000 mg) to each individual once a day under fasting,before the meal, immediately after the meal, or after the meal, at leastone value selected from the maximum plasma ω3PUFA concentrationcalculated by correcting the value by subtracting the blood ω3concentration before the administration, the plasma ω3PUFA concentration2 hours after the administration, the time required to reach the maximumplasma ω3PUFA concentration, the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration, the areaunder the curve of the plasma ω3PUFA concentration at 0 to 24 hoursafter the administration, maximum plasma concentration in steady state,minimum plasma concentration in steady state, and average plasmaconcentration in steady state is 70 to 1300 of the corresponding valueobtained by administering 1800 mg/day of the ω3PUFA (for example, Epadelcontaining the EPA-E) immediately after the meal.(9-14) A method for increasing the blood concentration according to theabove (9-1) to (9-13) wherein the maximum plasma ω3PUFA concentration isat least 50 μg/mL.(9-15) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-14) wherein the plasma ω3PUFA concentration2 hours after the administration is at least 20 μg/mL.(9-16) A method for increasing the blood concentration according to theabove (9-1) to (9-15) wherein the time required to reach the maximumplasma concentration is up to 6 hours.(9-17) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-16) wherein the area under the curve of theplasma ω3PUFA concentration at 0 to 72 hours after the administration isat least 500 μg·hr/mL.(9-18) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-17) wherein the area under the curve of theplasma ω3PUFA concentration at 0 to 24 hours after the administration isat least 100 μg·hr/mL.(9-19) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-18) wherein the maximum plasma ω3PUFAconcentration in steady state is at least 50 μg·hr/mL.(9-20) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-19) wherein the minimum plasma ω3PUFAconcentration in steady state is at least 10 μg·hr/mL.(9-21) A method for increasing the blood concentration according to anyone of the above (9-1) to (9-20) wherein the average ω3PUFA plasmaconcentration in steady state is at least 30 μg·hr/mL.

The tenth aspect of the present invention is the method as describedbelow.

(10-1) A method for reducing the side effects of ω3PUFA wherein at leastone compound selected from the group consisting of ω3PUFA and theirpharmaceutically acceptable salts and esters and lecithin areadministered in combination.(10-2) A method for reducing the side effects according to the above(10-1) wherein the ω3PUFA is administered at an individual daily dose of1800 mg or 2000 mg.(10-3) A method for reducing the side effects according to the above(10-1) or (10-2) wherein the ω3PUFA is administered at an individualdaily dose of 3600 mg or 4000 mg.(10-4) A method for reducing the side effects according to the above(10-1) wherein the ω3PUFA is administered at an individual daily dose ofat least 4000 mg.(10-5) A method for reducing the side effects according to any one ofthe above (10-1) to (10-4) wherein a polyoxyethylene sorbitan fatty acidester is further administered in combination.(10-6) A method for reducing the side effects according to any one ofthe above (10-1) to (10-5) wherein polyoxyethylene castor oil is furtheradministered in combination.(10-7) A method for reducing the side effects according to any one ofthe above (10-1) to (10-6) wherein 5 to 45 parts by weight of theemulsifier is administered in combination in relation to 100 parts byweight of the ω3PUFA.(10-8) A method for reducing the side effects according to the above(10-7) wherein up to 120 parts by weight of the polyoxyethylene castoroil is administered in combination in relation to 100 parts by weight ofthe polyoxyethylene sorbitan fatty acid ester.(10-9) A method for reducing the side effects according to any one ofthe above (10-1) to (10-8) wherein 1 to 25 parts by weight of lecithinis administered in combination with 100 parts by weight of the ω3PUFA.(10-10) A method for reducing the side effects according to any one ofthe above (10-1) to (10-9) wherein the ω3PUFA is administered once aday.(10-11) A method for reducing the side effects according to any one ofthe above (10-1) to (10-10) wherein the ω3PUFA is administered underfasting, before the meal, immediately after the meal, or after the meal.(10-12) A method for reducing the side effects according to any one ofthe above (10-1) to (10-11) wherein, when the ω3PUFA is administered atan individual dose of 500 to 10000 mg (for example, 1800 mg, 2000 mg)once a day under fasting, before the meal, immediately after the meal,or after the meal, at least one member selected from the maximum plasmaω3PUFA concentration calculated by correcting the value by subtractingthe plasma ω3PUFA concentration before the administration, the plasmaω3PUFA concentration 2 hours after the administration, the time requiredto reach the maximum plasma ω3PUFA concentration, and the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration is substantially the same as the corresponding valueobtained by administering 1800 mg/day of the ω3PUFA immediately afterthe meal.(10-13) A method for reducing the side effects according to any one ofthe above (10-1) to (10-12) wherein, when the ω3PUFA is administered atan individual dose of 500 to 10000 mg (for example, 1800 mg, 2000 mg)under fasting, before the meal, immediately after the meal, or after themeal, at least one value selected from the maximum plasma ω3PUFAconcentration calculated by correcting the value by subtracting theplasma ω3PUFA concentration before the administration, the plasma ω3PUFAconcentration 2 hours after the administration, the time required toreach the maximum plasma ω3PUFA concentration, and the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration is 70 to 130% of the corresponding value obtained byadministering 1800 mg/day of the ω3PUFA (for example, Epadel containingthe EPA-E) immediately after the meal.(10-14) A method for reducing the side effects according to any one ofthe above (10-1) to (10-13) wherein, when the ω3PUFA is administered atan individual dose of 500 to 10000 mg (for example, 1800 mg, 2000 mg)once a day under fasting, before the meal, immediately after the meal,or after the meal, at least one value selected from the maximum plasmaω3PUFA concentration calculated by correcting the value by subtractingthe plasma ω3PUFA concentration before the administration, the plasmaω3PUFA concentration 2 hours after the administration, the time requiredto reach the maximum plasma ω3PUFA concentration, the area under thecurve of the plasma ω3PUFA concentration at 0 to 72 hours after theadministration, the area under the curve of the plasma ω3PUFAconcentration at 0 to 24 hours after the administration, maximum ω3PUFAplasma concentration in steady state, minimum ω3PUFA plasmaconcentration in steady state, and average ω3PUFA plasma concentrationin steady state is substantially the same as the corresponding valueobtained by administering 1800 mg/day of the ω3PUFA immediately afterthe meal.(10-15) A method for reducing the side effects according to any one ofthe above (10-1) to (10-14) wherein, when the ω3PUFA is administered atan individual dose of 500 to 10000 mg (for example, 1800 mg, 2000 mg)under fasting, before the meal, immediately after the meal, or after themeal, at least one value selected from the maximum plasma ω3PUFAconcentration calculated by correcting the value by subtracting theplasma ω3PUFA concentration before the administration, the plasma ω3PUFAconcentration 2 hours after the administration, the time required toreach the maximum plasma ω3PUFA concentration, the area under the curveof the plasma ω3PUFA concentration at 0 to 72 hours after theadministration, the area under the curve of the plasma ω3PUFAconcentration at 0 to 24 hours after the administration, maximum ω3PUFAplasma concentration in steady state, minimum ω3PUFA plasmaconcentration in steady state, and average ω3PUFA plasma concentrationin steady state is 70 to 130% of the corresponding value obtained byadministering 1800 mg/day of the ω3PUFA (for example, Epadel containingthe EPA-E) immediately after the meal.(10-16) A method for reducing the side effects according to the above(10-1) to (10-15) wherein the maximum plasma ω3PUFA concentration is atleast 50 μg/mL.(10-17) A method for reducing the side effects according to any one ofthe above (10-1) to (10-16) wherein the plasma ω3PUFA concentration 2hours after the administration is at least 20 μg/mL.(10-18) A method for reducing the side effects according to the above(10-1) to (10-17) wherein the time required to reach the maximum plasmaω3PUFA concentration is up to 6 hours.(10-19) A method for reducing the side effects according to any one ofthe above (10-1) to (10-18) wherein the area under the curve of theplasma ω3PUFA concentration at 0 to 72 hours after the administration isat least 500 μg·hr/mL.(10-20) A method for reducing the side effects according to any one ofthe above (10-1) to (10-19) wherein the area under the curve of theplasma ω3PUFA concentration at 0 to 24 hours after the administration isat least 100 μg·hr/mL.(10-21) A method for reducing the side effects according to any one ofthe above (10-1) to (10-20) wherein the maximum plasma ω3PUFAconcentration in steady state is at least 50 μg·hr/mL.(10-22) A method for reducing the side effects according to any one ofthe above (10-1) to (10-21) wherein the minimum plasma ω3PUFAconcentration in steady state is at least 10 μg·hr/mL.(10-23) A method for reducing the side effects according to any one ofthe above (10-1) to (10-22) wherein the average ω3PUFA plasmaconcentration in steady state is at least 30 μg·hr/mL.

The eleventh aspect of the present invention is the self-emulsifyingcomposition or the method as described below.

(11-1) A self-emulsifying composition or its administration methodwherein, when the composition comprising at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters, as well as lecithin and/or apolyoxyethylene sorbitan fatty acid ester as the emulsifier, isadministered at an individual dose of 500 to 10000 mg in terms of theω3PUFA, the maximum plasma ω3PUFA concentration under fasting calculatedby correcting the value by subtracting the plasma ω3PUFA concentrationbefore the administration is 70 to 130% of the maximum plasma ω3PUFAconcentration immediately after the meal.(11-2) A self-emulsifying composition or its administration methodwherein, when the composition comprising at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters, as well as lecithin and/or an emulsifier,is administered at an individual dose of 500 to 10000 mg in terms of theω3PUFA, the maximum plasma ω3PUFA concentration under fasting calculatedby correcting the value by subtracting the plasma ω3PUFA concentrationbefore the administration is 70 to 130% of the maximum plasma ω3PUFAconcentration immediately after the meal.(11-3) A self-emulsifying composition or its administration methodaccording to the above (11-1) or (11-2) wherein the emulsifier is atleast one member selected from cationic surfactant, anionic surfactant,amphoteric surfactant, and nonionic surfactant.(11-4) A self-emulsifying composition or its administration methodaccording to the above (11-3) wherein the nonionic surfactant is apolyoxyethylene sorbitan fatty acid ester.(11-5) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-4) wherein thecomposition is administered once a day.(11-6) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-5) wherein thecomposition is administered under fasting, before the meal, immediatelyafter the meal, or after the meal.(11-7) A self-emulsifying composition or its administration methodaccording to the above (11-1) to (11-6) wherein the maximum plasmaω3PUFA concentration is at least 50 μg/mL.(11-8) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-7) wherein the plasmaω3PUFA concentration 2 hours after the administration is at least 20μg/mL.(11-9) A self-emulsifying composition or its administration methodaccording to the above (11-1) to (11-8) wherein the time required toreach the maximum plasma ω3PUFA concentration is up to 6 hours.(11-10) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-9) wherein the areaunder the curve of the plasma ω3PUFA concentration at 0 to 72 hoursafter the administration is at least 500 μg·hr/mL.(11-11) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-10) wherein the areaunder the curve of the plasma ω3PUFA concentration at 0 to 24 hoursafter the administration is at least 100 μg·hr/mL.(11-12) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-11) wherein the maximumplasma ω3PUFA concentration in steady state is at least 50 μg·hr/mL.(11-13) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-12) wherein the minimumplasma ω3PUFA concentration in steady state is at least 10 μg·hr/mL.(11-14) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-13) wherein the averageω3PUFA plasma concentration in steady state is at least 30 μg·hr/mL.(11-15) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-14) wherein the ω3PUFAand their pharmaceutically acceptable salts and esters administered areat least one member selected from the group consisting of EPA and itspharmaceutically acceptable salts and esters.(11-16) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-15) wherein content ofthe at least one compound selected from the group consisting of ω3PUFAand their pharmaceutically acceptable salts and esters is 70 to 90% byweight when total amount of the self-emulsifying composition is 100% byweight.(11-17) A self-emulsifying composition or its administration methodaccording to the above (11-15) wherein the EPA and its pharmaceuticallyacceptable salts and esters are ethyl ester of EPA.(11-18) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-17) wherein content ofthe at least one compound selected from the group consisting of EPA andits pharmaceutically acceptable salts and esters is 70 to 90% by weightwhen total amount of the self-emulsifying composition is 100% by weight.(11-19) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-18) wherein thecomposition contains lecithin and a nonionic surfactant as theemulsifier.(11-20) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-19) wherein thecomposition contains lecithin and a polyoxyethylene sorbitan fatty acidester as the emulsifier.(11-21) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-20) wherein thecomposition contains lecithin and a polyoxyethylene sorbitan fatty acidester as the nonionic surfactant.(11-22) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-21) wherein thecomposition further contains polyoxyethylene castor oil as theemulsifier.(11-23) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-22) wherein content ofthe emulsifier is 1 to 29% by weight when total amount of theself-emulsifying composition is 100% by weight.(11-24) A self-emulsifying composition or its administration methodaccording to any one of the above (11-1) to (11-23) wherein content ofthe polyoxyethylene castor oil is up to 120 parts by weight in relationto 100 parts by weight of the polyoxyethylene sorbitan fatty acid esterin the composition.

The twelfth aspect of the present invention is the self-emulsifyingcomposition as described below.

(12-1) A self-emulsifying composition containing at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or a polyoxyethylenesorbitan fatty acid ester as an emulsifier, wherein maximum plasmaω3PUFA concentration determined by administering the compositioncontaining 3600 mg/individual of ω3PUFA and conducting the correction bysubtracting the plasma ω3PUFA concentration before the administration isat least 1.2 times as high as the maximum plasma ω3PUFA concentrationdetermined by administering the composition containing 1800mg/individual of ω3PUFA.(12-2) A self-emulsifying composition containing at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters as well as lecithin and/or a polyoxyethylenesorbitan fatty acid ester as an emulsifier, wherein maximum plasmaω3PUFA concentration determined by administering the compositioncontaining 4000 mg of ω3PUFA and conducting the correction bysubtracting the plasma ω3PUFA concentration before the administration isat least 1.2 times as high as the maximum plasma ω3PUFA concentrationdetermined by administering the composition containing 2000 mg ofω3PUFA.(12-3) A self-emulsifying composition according to the above (12-1) or(12-2) wherein the maximum plasma ω3PUFA concentration is at least 50μg/mL.(12-4) A self-emulsifying composition according to the above (12-1) to(12-3) wherein the plasma ω3PUFA concentration 2 hours after theadministration is at least 20 μg/mL.(12-5) self-emulsifying composition according to any one of the above(12-1) to (12-4) wherein the time required to reach the maximum plasmaω3PUFA concentration is up to 6 hours.(12-6) A self-emulsifying composition according to any one of to theabove (12-1) to (12-5) wherein the area under the curve of the plasmaω3PUFA concentration at 0 to 72 hours after the administration is atleast 500 μg·hr/mL.(12-7) A self-emulsifying composition according to any one of the above(12-1) to (12-6) wherein the ω3PUFA and their pharmaceuticallyacceptable salts and esters administered are at least one memberselected from the group consisting of EPA and its pharmaceuticallyacceptable salts and esters.(12-8) A self-emulsifying composition according to any one of to theabove (12-1) to (12-7) wherein content of the at least one compoundselected from the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters is 70 to 90% by weight when total amount ofthe self-emulsifying composition is 100% by weight.(12-9) A self-emulsifying composition according to the above (12-8)wherein EPA and its pharmaceutically acceptable salts and esters areethyl ester of EPA.(12-10) A self-emulsifying composition according to any one of the above(12-1) to (12-9) wherein content of the at least one compound selectedfrom the group consisting of EPA and its pharmaceutically acceptablesalts and esters is 70 to 90% by weight when total amount of theself-emulsifying composition is 100% by weight.(12-11) A self-emulsifying composition according to any one of the above(12-1) to (12-10) wherein the composition contains lecithin andpolyoxyethylene sorbitan fatty acid ester as the emulsifier.(12-12) A self-emulsifying composition according to the above (12-1) to(12-11) wherein the composition further contains polyoxyethylene castoroil as the emulsifier.(12-13) A self-emulsifying composition according to the above (12-1) to(12-12) wherein content of the polyoxyethylene castor oil is up to 120parts by weight in relation to 100 parts by weight of thepolyoxyethylene sorbitan fatty acid ester in the composition.(12-14) A self-emulsifying composition according to any one of the above(12-1) to (12-13) wherein the content of the emulsifier is 1 to 29% byweight when total amount of the self-emulsifying composition is 100% byweight.(12-15) A self-emulsifying composition according to any one of the above(12-1) to (12-14) wherein content of the lecithin is 3 to 40 parts byweight or 1 to 25 parts by weight in relation to 100 parts by weight ofthe at least one compound selected from the group consisting of ω3PUFAand their pharmaceutically acceptable salts and esters.

The thirteenth aspect of the present invention is an emulsionpreparation prepared by dispersing the self-emulsifying composition inan aqueous solution as described below.

(13-1) An emulsion preparation containing at least one compound selectedfrom the group consisting of ω3PUFA and their pharmaceuticallyacceptable salts and esters, as well as lecithin and/or apolyoxyethylene sorbitan fatty acid ester as an emulsifier

Advantageous Effects of Invention

The self-emulsifying composition of the present invention contains asmall amount of water instead of the ethanol and the polyhydric alcoholin its composition. Compatibility of the composition improves by suchcomposition, and amount of the emulsifier used can also be reduced, andaccordingly, safety for animals (including human) is thereby improved.In addition, the ω3 PUFA will be included at a higher content, and thisenables reduction in the amount of emulsifier used, and compliance isthereby improved.

Inclusion of the water in the composition also enables a compositionwithout or with minimized use of the ethanol or the polyhydric alcohols,and hence, prevention of the softening of the capsule film, anddeformation of the capsule. A preparation with minimized use of theethanol and the polyhydric alcohols can also be obtained. A preparationwhich is excellent in drug compliance or drug adherence can also beobtained.

The self-emulsifying composition of the present invention is excellentin at least one of compatibility (appearance), self-emulsifyingproperty, dispersibility of the composition, emulsion stability, andabsorbability, is rapidly absorbed even if administered before the mealor after the low-fat meal to thereby suppress an increase in the serumTG after the meal, increases the ω3PUFA concentration in blood (the term“in blood” means “in whole blood, plasma, or serum” and this alsoapplies to the following description), or is administered before goingto bed to thereby prevent essential fatty acid deficiency uponadministration of the lipase inhibitor.

The self-emulsifying composition of the present invention reduces theamount of the ω3PUFA that is not absorbed and then egested afteradministration, enhances tissue migration properties of the ω3PUFA,increases the uptake of ω3PUFA into phospholipid in blood, oralternatively decreases arachidonic acid in blood and/or improves theEPA/AA ratio.

The self-emulsifying composition enables not only the storage at roomtemperature but also the storage under the conditions of low temperature(for example, 5° C.) and high temperature (for example, 40° C.) withoutcausing separation or cloudiness of the composition, namely, with goodappearance. The self-emulsifying composition of the present invention isalso excellent in at least one of self-emulsifying property,dispersibility of the composition, emulsion stability, andabsorbability.

The self-emulsifying composition of the present invention has storagestability at at least one of room temperature, low temperature and hightemperature, has storage stability at at least one specific temperatureselected from the temperature of from, for example, 5° C. to 40° C.,does not change the parameters to cause stable quality as apharmaceutical product to deteriorate if stored in at at least one ofroom temperature, low temperature and high temperature, or does notchange the parameters to cause stable quality as a pharmaceuticalproduct to deteriorate if stored at at least one specific temperatureselected from the temperature of from, for example, 5° C. to 40° C.

The self-emulsifying composition of the present invention as aboveenables a preparation with improved absorption of the ω3PUFA, the samepharmacokinetics as the conventional pharmacokinetics in theadministration of the ω3PUFA preparation immediately after the meal evenif administered at a smaller dose of the ω3PUFA, or absorption of theω3PUFA not or little affected by the meal.

The self-emulsifying composition exhibits good absorption of the ω3PUFAirrespective of timing of the administration whether the administrationis carried out in the fasting, before the meal, or after the low-fatmeal, and the limitation for the administration timing is reducedcompared to conventional ω3PUFA preparations (for example, Epadel andLotriga) that requires the administration immediately after the meal,and absorption efficiency was not affected by the meal.

The self-emulsifying composition exhibits high absorption, andtherefore, it has high therapeutic effects, and the amount of the ω3PUFArequired for the treatment can be reduced.

When the ω3PUFA is administered at a high dose (for example, 4000mg/day/individual) to gain high therapeutic effects, the excessiveω3PUFA that is not absorbed by human remains in the intestinal tract,and side effects of lower gastrointestinal tract and the like werethereby induced. In contrast, since the self-emulsifying composition ofthe present invention is highly absorbable, and remaining ω3PUFA stayingin the intestinal tract can be reduced or eliminated, the side effectswill be reduced. In addition, since the self-emulsifying composition ofthe present invention is absorbable even in the administration of thedose at which sole administration of the ω3PUFA would result in thesaturation of the blood concentration, the blood concentration can beincreased beyond the blood concentration in the sole administration ofthe ω3PUFA.

By administration, the self-emulsifying composition of the presentinvention is capable of improving (reducing) at least one parameterselected from TG, T-cho, LDL-C, non-HDL-C, VLDL-C, VLDL-TG, oxidizedLDL, small dense LDL, RLP-C, ApoB, ApoCIII, lipoprotein (a), Lp-PLA2,CETP activity, hs-CRP, plasma phospholipid, free fatty acid, fastingblood glucose, HbA1c, HOMA-IR, intercellular adhesion molecule-1, IL-6,PAI-1, creatinine, AST, ALT, uric acid, 8-isoprostane, TXA2 and LTB2 andthe metabolites thereof (HETE), and the like. The self-emulsifyingcomposition of the present invention is also capable of improving(increasing) at least one parameter selected from HDL-C, apoA-I,apoA-I/ApoB ratio, EPA in the plasma, serum, erythrocyte membrane orplatelet membrane. The self-emulsifying composition of the presentinvention is also capable of reducing the number of LDL particles,increasing LDL particle size, and improving at least one parameterselected from ApoE genotype abnormality, hemoglobin abnormality,hematocrit abnormality, thrombocyte abnormality, and the like.

In the self-emulsifying composition of the present invention, thecomposition has stable quality. The self-emulsifying composition of thepresent invention has storage stability immediately after its productionor for any long period of, for example, three or five years after itsproduction, or does not change the parameters to cause stable quality asa pharmaceutical product to deteriorate immediately after its productionor if stored for any long period of, for example, three or five yearsafter its production.

The present invention can provide an emulsion with improved absorptionof the ω3PUFA in the composition, a self-emulsifying composition forenabling quick production of the emulsion, and a method for producingthe emulsion.

The self-emulsifying composition of the present invention has at leastone, preferably at least two, and more preferably all of the preferablefeatures as described above.

DESCRIPTION OF EMBODIMENTS

Next, the present invention is described in detail.

The present invention relates to a self-emulsifying compositioncomprising 70 to 90% by weight in total of at least one compoundselected from the group consisting of ω3 polyunsaturated fatty acid, itspharmaceutically acceptable salts, and its esters, 1 to 29% by weight ofa particular emulsifying agent, and 3 to 40 parts by weight or 1 to 25parts by weight of lecithin in relation to 100 parts by weight of the ω3polyunsaturated fatty acid, its pharmaceutically acceptable salt, orester, wherein the composition has low or no content of ethanol orpolyhydric alcohol. The present invention also relates to aself-emulsifying preparation having such self-emulsifying compositionencapsulated therein, and a pharmaceutical product, a production method,and a method of use thereof.

In the present invention, “ω3 PUFA” is a fatty acid having a pluralityof carbon—carbon double bonds in the molecule, and the first double bondis at 3rd position from the end on the side of the methyl group. Typicalexamples include α-linolenic acid, EPA, DHA, eicosatrienoic acid,stearidonic acid, eicosatetraenoic acid, clupanodonic acid,tetracosapentaenoic acid, and nisinic acid. Unless otherwise noted, theterms “ω3 PUFA”, “EPAs”, “DHAs”, and “fatty acids” as used in thepresent invention mean not only an ω3 PUFA, an EPA, a DHA, and a fattyacid but also pharmaceutically acceptable salts and esters thereof.

The ω3 PUFA used in the present invention may be a synthetic,semi-synthetic, natural ω3 PUFA, or a natural oil containing such ω3PUFA. Examples of the natural ω3 PUFA include an extract from a naturaloil containing an ω3 PUFA, a crudely purified natural oil containing anω3 PUFA, and a highly purified natural oil containing an ω3 PUFAproduced by a method known in the art. Exemplary semi-synthetic ω3 PUFAsinclude ω3 PUFAs produced by a microorganism or the like and the ω3PUFAs or the natural ω3 PUFAs which have been subjected to a chemicaltreatment such as esterification or ester exchange. In the presentinvention, the ω3 PUFAs may be used alone or in combination of two ormore.

In the present invention, EPAs and DHAs are the preferable examples ofthe ω3 PUFAs, and EPAs are more preferable. Examples of thepharmaceutically acceptable salts of the ω3 PUFA include inorganic saltssuch as sodium salts and potassium salts, organic salts such asbenzylamine salts and diethylamine salts, salts with basic amino acidssuch as arginine salts and lysine salts, and exemplary esters includealkyl esters such as ethyl ester, and esters such as monoglyceride (MG),diglyceride (DG) and triglyceride (TG). Preferable examples includeethyl ester and TG ester, and the more preferred is ethyl ester. Morespecifically, preferable examples include EPA-E, TG ester of EPA, DHA-E,and TG ester of DHA, and among these, the more preferred are EPA-E andDHA-E, and the most preferred is EPA-E.

The ω3 PUFA used for the starting material of the self-emulsifyingcomposition of the present invention is not particularly limited for itspurity. The purity is typically such that content of the ω3 PUFAs in thetotal fatty acids of the composition of the present invention could bepreferably at least 50% by weight, more preferably at least 70% byweight, still more preferably at least 80% by weight, still morepreferably at least 90% by weight, still more preferably at least 96.5%by weight, and most preferably at least 98% by weight. The ω3 PUFAscontaining the EPAs at a high purity, for example, the one with the EPAscontent of at least 50% by weight in relation to the ω3 PUFAs ispreferable, and the content is more preferably at least 60% by weight,still more preferably at least 70% by weight, still more preferably atleast 80% by weight, still more preferably at least 90% by weight, andmost preferably at least 98% by weight. In other words, the compositionof the present invention preferably has a high purity of ω3 PUFAs in thetotal fatty acid, more preferably, a high purity of EPAs and DHAs whichare ω3 PUFAs, and most preferably an EPA purity with substantially noDHA or with the DHA of, for example less than 1.0% by weight, preferablyless than 0.5% by weight, and more preferably less than 0.2% by weight

For example, when EPA-E and DHA-E are used, compositional ratio ofEPA-E/DHA-E and content of (EPA-E+DHA-E) in relation to total fatty acidare not particularly limited as long as the purity of EPA-E in thecomposition of the present invention is in the range as described above.However, the compositional ratio of the EPA-E/DHA-E is preferably atleast 0.8, more preferably at least 1.0, and most preferably at least1.2.

The composition of the present invention may also contain apolyunsaturated fatty acid other than the ω3 PUFA such as linoleic acid,γ linolenic acid, or dihomo-γ-linolenic acid or the pharmaceuticallyacceptable salt or ester thereof. However, content of arachidonic acidor the pharmaceutically acceptable salt or ester thereof is preferablylow, more preferably less than 2% by weight, still more preferably lessthan 1% by weight, and most preferably, the composition is substantiallyfree from the arachidonic acid or the pharmaceutically acceptable saltor ester thereof.

In the self-emulsifying composition of the present invention, content ofthe ω3 PUFA is 50 to 95% by weight, 60 to 92% by weight, 70 to 90% byweight, and preferably 70 to 86% by weight, more preferably 72 to 85% byweight, and still more preferably 74 to 84% by weight. The ω3PUFAs usedmay comprise a single compound or a mixture of two or more compounds. Inthe case of the mixture of two or more compounds, total content of themixture is 70 to 90% by weight of the self-emulsifying composition.

The ω3 PUFA used may be a soft capsule containing the EPA-E at a highpurity (at least 96.5% by weight) (product name, Epadel; manufactured byMochida Pharmaceutical Co., Ltd.) commercially available in Japan as atherapeutic agent for ASO and hyperlipidemia or a high purity EPA-Econtaining capsule (product name, VASCEPA; Amarin) commerciallyavailable in the U.S. as a therapeutic agent for hypertriglyceridemia.The ω3 PUFA used may also be a mixture of EPA-E and DHA-E, for example,Lovaza (Registered Trademark) (a soft capsule containing about 46.5% byweight of EPA-E and about 37.5% by weight of DHA-E from GlaxoSmithKline)commercially available in the U.S. as a therapeutic agent forhypertriglyceridemia or LOTRIGA (Registered Trademark) (a soft capsulecontaining about 46.5% by weight of EPA-E and about 37.5% by weight ofDHA-E from Takeda Pharmaceutical Co., Ltd.) commercially available inJapan. The mixture of EPA and DHA used may be, for example, EPANOVA(Registered Trademark) (a soft capsule containing about 50 to 60% byweight of EPA free acid and about 15 to 25% by weight of DHA free acidfrom AstraZeneca) commercially available in the U.S. as a therapeuticagent for hypertriglyceridemia.

Purified fish oils may also be used for the ω3 PUFA, and uses ofmonoglyceride (MG), diglyceride (DG), and TG derivatives andcombinations thereof as the ω3 PUFA are also preferable embodiments.Various products containing the ω3 PUFA are commercially available, forexample, Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928,TG3525, and E5015 (Croda International PLC, Yorkshire, England), andEPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, K85TG,K85EE, and K80EE (Pronova Biopharma, Lysaker, Norway). These productsmay be purchased and used for the composition of the present invention.

In the present invention, the “polyoxyethylene sorbitan fatty acidester” is polyoxyethylene ether of a fatty acid ester wherein a part ofthe hydroxy groups of anhydrous sorbitol have been esterified with afatty acid. Various compounds with different esterifying fatty acids arecommercially available, and examples include polyoxyethylene (20)sorbitan monolaurate (NIKKOL TL-10, polysorbate 20, Tween 20),polyoxyethylene (20) sorbitan monopalmitate (NIKKOL TP-10V, Polysorbate40, Tween 40), polyoxyethylene (20) sorbitan monostearate (NIKKOLTS-10MV, polysorbate 60, Tween 60), polyoxyethylene (20) sorbitantristearate (NIKKOL TS-30V, polysorbate 65), polyoxyethylene (20)sorbitan monoisostearate (NIKKOL TI-10V), polyoxyethylene (20) sorbitanmonooleate (NIKKOL TO-10MV, polysorbate 80, Tween 80), andpolyoxyethylene (20) sorbitan trioleate (NIKKOL TO-30V, polysorbate 85),and the preferred are polyoxyethylene (20) sorbitan monooleate, andpolyoxyethylene (20) sorbitan trioleate, and the more preferred ispolyoxyethylene (20) sorbitan monooleate.

These may be used alone or in combination of two or more. The term“polyoxyethylene sorbitan fatty acid ester” as used in the presentinvention means all of such compounds.

Content of the polyoxyethylene sorbitan fatty acid ester in theself-emulsifying composition of the present invention is notparticularly limited as long as the merits of the present invention arenot adversely affected. The content is generally 1 to 29% by weight,preferably 3 to 20% by weight, more preferably 5 to 15% by weight, andmost preferably 5 to 9% by weight when the total amount of theself-emulsifying composition is 100% by weight.

In the present invention, the “polyoxyethylene castor oil” is a compoundprepared by addition polymerization of ethylene oxide to castor oil.Various compounds with different average ethylene oxide mole numbers arecommercially available, and examples include NIKKOL CO-3 (NikkoChemicals Co., Ltd.) with an average ethylene oxide mole number of 3,NIKKOL CO-10 (Nikko Chemicals Co., Ltd.) with an average ethylene oxidemole number of 10, EMALEX C-(Nippon Emulsion Co., Ltd.) with an averageethylene oxide mole number of 20, EMALEX C-30 (Nippon Emulsion Co.,Ltd.) with an average ethylene oxide mole number of 30, Kolliphor EL(BASF) (polyoxyl 35 castor oil) with an average ethylene oxide molenumber of 35, EMALEX C-40 (Nippon Emulsion Co., Ltd.) with an averageethylene oxide mole number of 40, and EMALEX C-50 (Nippon Emulsion Co.,Ltd.) with an average ethylene oxide mole number of 50, and thepreferred is Kolliphor EL. These may be used alone or in combination oftwo or more. The term “polyoxyethylene castor oil” as used in thepresent invention means all of such compounds unless otherwise noted.

Content of the polyoxyethylene castor oil in the self-emulsifyingcomposition of the present invention is not particularly limited in thepresent invention as long as the merits of the present invention are notadversely affected. The content is generally 1 to 20% by weight,preferably 2 to 15% by weight, more preferably 3 to 10% by weight, andmost preferably 5 to 9% by weight when the total amount of theself-emulsifying composition is 100% by weight. The content of thepolyoxyethylene castor oil in relation to 100 parts by weight of thepolyoxyethylene sorbitan fatty acid ester in the composition ispreferably up to 150 parts by weight, preferably up to 140 parts byweight, more preferably up to 130 parts by weight, still more preferablyup to 120 parts by weight, particularly preferably up to 110 parts byweight, and most preferably up to 100 parts by weight. Thepolyoxyethylene sorbitan fatty acid ester and the polyoxyethylene castoroil are preferably incorporated so that content ratio of thepolyoxyethylene sorbitan fatty acid ester to the polyoxyethylene castoroil in the composition is 100 parts by weight: 5 to 150 parts by weight,preferably 100 parts by weight: 10 to up to 140 parts by weight, morepreferably 100 parts by weight: 20 to up to 130 parts by weight andstill more preferably 100 parts by weight: 30 to 120 parts by weight,still more preferably 100 parts by weight: 50 to 110 parts by weight,and most preferably 100 parts by weight: 80 to 120 parts by weight.

In the present invention, the “polyoxyethylene hydrogenated castor oil”is a compound prepared by hydrogenating castor oil with hydrogen, andsubjecting the resulting hydrogenated castor oil to additionpolymerization with ethylene oxide. Various compounds having differentaverage degrees of polymerization of ethylene oxide are commerciallyavailable, and examples include polyoxyethylene (20) hydrogenated castoroil (NIKKOL HCO-20, Nikko Chemicals Co., Ltd.), polyoxyethylene (40)hydrogenated castor oil (NIKKOL HCO-40, Nikko Chemicals Co., Ltd.),polyoxyethylene (50) hydrogenated castor oil (NIKKOL HCO-50, NikkoChemicals Co., Ltd.), polyoxyethylene (60) hydrogenated castor oil(NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), and polyoxyethylene (100)hydrogenated castor oil (NIKKOL HCO-100, Nikko Chemicals Co., Ltd.), andthe preferred is, for example, polyoxyethylene (60) hydrogenated castoroil. These may be used alone or in combination of two or more. Unlessotherwise noted, the term “polyoxyethylene hydrogenated castor oil” ofthe present invention includes all of such compounds.

Content of the polyoxyethylene hydrogenated castor oil in theself-emulsifying composition of the present invention is notparticularly limited as long as the intended merits of the presentinvention is realized. The content, however, is generally 1 to 20% byweight, preferably 2 to 15% by weight, more preferably 3 to 10% byweight, and most preferably 5 to 9% by weight when the total amount ofthe self-emulsifying composition is 100% by weight. In addition, thepolyoxyethylene hydrogenated castor oil is preferably incorporated inthe composition at a proportion in relation to 100 parts by weight ofthe polyoxyethylene sorbitan fatty acid ester of up to 150 parts byweight, preferably up to 140 parts by weight, more preferably up to 130parts by weight, still more preferably up to 120 parts by weight, stillmore preferably up to 110 parts by weight, and most preferably up to 100parts by weight. The polyoxyethylene sorbitan fatty acid ester and thepolyoxyethylene castor oil are preferably incorporated so that contentratio of the polyoxyethylene sorbitan fatty acid ester to thepolyoxyethylene hydrogenated castor oil in the composition is 100 partsby weight: 5 to 150 parts by weight, preferably 100 parts by weight: 10to up to 140 parts by weight, more preferably 100 parts by weight: 20 toup to 130 parts by weight and still more preferably 100 parts by weight:30 to 120 parts by weight, still more preferably 100 parts by weight: 50to 110 parts by weight, and most preferably 100 parts by weight: 80 to120 parts by weight.

In the present invention, the term “emulsifier” includes surfactants.The surfactant may be selected from cationic surfactant, anionicsurfactant, amphoteric surfactant, nonionic surfactant, and the like,and the preferred is nonionic surfactant. Exemplary known nonionicsurfactants include polyoxyethylene sorbitan fatty acid ester, sorbitanfatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester,polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.

The self-emulsifying composition of the present invention has thecharacteristic feature in that it contains the polyoxyethylene sorbitanfatty acid ester as the emulsifier. In one of the preferred embodimentsof the present invention, the composition contains polyoxyethylenesorbitan fatty acid ester and polyoxyethylene castor oil and/orpolyoxyethylene hydrogenated castor oil as the emulsifiers. In anotherpreferred embodiment of the present invention, the composition containspolyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oilas the emulsifiers. The self-emulsifying composition of the presentinvention may contain an emulsifier other than polyoxyethylene sorbitanfatty acid ester and polyoxyethylene castor oil for the emulsifier, andthe content is up to 20 parts by weight, more preferably up to 10 partsby weight, still more preferably less than 5 parts by weight, and mostpreferably substantially zero when total content of the emulsifier usedin the composition is 100 parts by weight. The emulsifier which may beadditionally incorporated is not particularly limited as long as atleast one of the problems as described above can be solved, and examplesinclude sorbitan fatty acid ester, glycerin fatty acid ester,polyoxyethylene hydrogenated castor oil, propylene glycol fatty acidester, saturated polyglycolated glyceride, polyoxyethylenepolyoxypropylene glycol, sucrose fatty ester, polyethylene glycol fattyacid ester, tocopherol—polyethylene glycol—succinic acid ester (TPGS),and the like.

The total content of the emulsifier in the self-emulsifying compositionof the present invention is not particularly limited as long as theintended effects of the present invention are realized. However, whenthe total amount of the self-emulsifying composition is 100% by weight,the total content of the emulsifier is 1 to 29% by weight, preferably 3to 27% by weight, more preferably 5 to 27% by weight, still morepreferably 5 to 24% by weight, and most preferably 10 to 20% by weight.Alternatively, the total content is preferably 8 to 27% by weight, andmore preferably 10 to 27% by weight. In addition, the total content inrelation to 100 parts by weight of the ω3PUFA is 5 to 45 parts byweight, preferably 10 to 45 parts by weight, more preferably 15 to 35parts by weight, and most preferably 15 to 20 parts by weight.

The composition and the pharmaceutical preparation of the presentinvention contain a small amount of water. Addition of water to acomposition containing a hydrophobic lipid is generally conceived as aloss of compatibility. Presence of water in the composition results inthe improved compatibility of the composition, and the use of thepolyhydric alcohol and the ethanol becomes unnecessary. In other words,a product having transparent appearance which is free from the problemof separation or cloudiness of the composition is produced without usingthe polyhydric alcohol or the ethanol.

The small amount of water may be added during the preparation of theself-emulsifying composition, and the water in the gelatin capsule filmmay transfer to the self-emulsifying composition after the encapsulationof the self-emulsifying composition in the gelatin capsule.

In addition, the composition free from the polyhydric alcohol and theethanol neither causes the capsule to be softened or deformed after theencapsulation, nor has side effects of the ethanol on alcoholintolerance patients taking the composition.

The water is preferably used at an amount of 0.5 to 6% by weight, morepreferably at 0.5 to 4% by weight, more preferably at 0.5 to 3% byweight, and most preferably at 1 to 3% by weight when the total amountof the self-emulsifying composition is 100% by weight. Alternatively,the water is preferably used at an amount of at least 0.5% by weight andless than 3% by weight, and more preferably at least 0.5% by weight andless than 1.5% by weight.

Specifically, the water is also preferably used at, but not limited to,an amount of, for example, 0.5% by weight, 0.55% by weight, 0.6% byweight, 0.65% by weight, 0.7% by weight, 0.75% by weight, 0.8% byweight, 0.85% by weight, 0.9% by weight, 0.95% by weight, 1.0% byweight, 1.1% by weight, 1.2% by weight, 1.3% by weight, 1.4% by weight,1.5% by weight, 1.6% by weight, 1.7% by weight, 1.8% by weight, 1.9% byweight, 2.0% by weight, 2.1% by weight, 2.2% by weight, 2.3% by weight,2.4% by weight, 2.5% by weight, 2.6% by weight, 2.7% by weight, 2.8% byweight, 2.9% by weight, 3.0% by weight, 3.1% by weight, 3.2% by weight,3.3% by weight, 3.4% by weight, 3.5% by weight, 3.6% by weight, 3.7% byweight, 3.8% by weight, 3.9% by weight, 4.0% by weight, 4.1% by weight,4.2% by weight, 4.3% by weight, 4.4% by weight, 4.5% by weight, 4.6% byweight, 4.7% by weight, 4.8% by weight, 4.9% by weight, 5.0% by weight,5.1% by weight, 5.2% by weight, 5.3% by weight, 5.4% by weight, 5.5% byweight, 5.6% by weight, 5.7% by weight, 5.8% by weight, 5.9% by weightand 6.0% by weight when the total amount of the self-emulsifyingcomposition is 100% by weight.

In the present invention, the “lecithin” is one type ofglycerophospholipid, and examples include soybean lecithin, zymolyticsoybean lecithin, hydrogenated soybean lecithin, soybean phospholipid,purified soybean phospholipid, hydrogenated soybean phospholipid, eggyolk lecithin, egg yolk phopholipid, hydrogenated phospholipid,phospholipid from milk, high purity synthetic phospholipid, unsaturatedphospholipid, lysolecithin, phospholipid premix, phosphatidic acid,phosphatidylethanolamine, phosphatidylcholine (purifiedphosphatidylcholine, purified egg yolk phosphatidylcholine, hydrogenatedphosphatidylcholine, polyenephosphatidylcholine, and hydrogenatedpurified egg yolk phosphatidylcholine), phosphatidylserine,phosphatidylglycerol (purified phosphatidylglycerol, purified egg yolkphosphatidylglycerol, hydrogenated phosphatidylglycerol),phosphatidylinocitol, cardiolipin, α-glycerophosphocholine, and purifiedegg yolk sphingomyelin. The preferred are soybean lecithin, zymolyticsoybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin,and the more preferred is soybean lecithin. These may be used alone orin combination of two or more. The term “lecithin” as used in thepresent invention means all of such glycerophospholipids unlessotherwise noted. In the present invention, lecithin is not included inthe emulsifier (namely, not in the “emulsifier” as the constituent ofthe invention, and not taken into account in the calculation of thecontent of the emulsifier in the composition).

Various products of lecithins are commercially available, and exemplarysuch products include purified soybean lecithin (Nisshin Oilio),purified egg yolk lecithin (Asahi Kasei Pharma Corporation), and eggyolk lecithin PL-100M (Kewpie Corporation). Exemplary soybean lecithinsinclude BASIS LP-20B (Nisshin Oil Mills, Ltd.) and Lipoid S45 and S20(Lipoid), and exemplary zymolytic lecithins include BASIS LP-20E(Nisshin Oil Mills, Ltd.) and Phospholipon RLPC20 (Lipoid). Various suchcommercially available products may be used in the composition.

The content of the lecithin added in the self-emulsifying composition ofthe present invention is not particularly limited. The content inrelation to 100 parts by weight of the ω3PUFAs is, however, preferably0.5 to 40 parts by weight, more preferably 1 to 40 parts by weight,still more preferably 2 to 40 parts by weight, still more preferably 3to 40 parts by weight, still more preferably 3 to 30 parts by weight,still more preferably 3 to 25 parts by weight, still more preferably 3to 20 parts by weight, still more preferably 3.2 to 17 parts by weight,still more preferably 3.5 to 15 parts by weight, and still morepreferably 3.7 to 17 parts by weight. Alternatively, the content ispreferably 3 to 15 parts by weight, more preferably 3 to 12 parts byweight, and still more preferably 3 to 10 parts by weight. Mostpreferably, the content is 5 to 10 parts by weight.

The content of the lecithin is preferably 2.1 to 36% by weight, morepreferably 2.1 to 20% by weight, and still more preferably 2.1 to 15% byweight when the total amount of the self-emulsifying composition is 100%by weight. Alternatively, the content is preferably 0.5 to 30% byweight, more preferably 1 to 25% by weight, still more preferably 1 to20% by weight, and still more preferably 2 to 15% by weight. Mostpreferably, the content is 2.1 to 10% by weight.

Specifically, the content of the lecithin is also preferably, but notlimited to, for example, 0.5% by weight, 0.6% by weight, 0.7% by weight,0.8% by weight, 0.9% by weight, 1.0% by weight, 1.1% by weight, 1.3% byweight, 1.5% by weight, 1.7% by weight, 1.9% by weight, 2.1% by weight,2.3% by weight, 2.5% by weight, 2.7% by weight, 2.9% by weight, 3.1% byweight, 3.3% by weight, 3.5% by weight, 3.7% by weight, 3.9% by weight,4.1% by weight, 4.3% by weight, 4.5% by weight, 4.7% by weight, 4.9% byweight, 5.1% by weight, 5.3% by weight, 5.5% by weight, 5.7% by weight,5.9% by weight, 6.1% by weight, 6.3% by weight, 6.5% by weight, 6.7% byweight, 6.9% by weight, 7.1% by weight, 7.3% by weight, 7.5% by weight,7.7% by weight, 7.9% by weight, 8.1% by weight, 8.3% by weight, 8.5% byweight, 8.7% by weight, 8.9% by weight, 9.1% by weight, 9.3% by weight,9.5% by weight, 9.7% by weight, 9.9% by weight, 10% by weight, 11% byweight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16%by weight, 17% by weight, 18% by weight, 19% by weight and 20% by weightwhen the total amount of the self-emulsifying composition is 100% byweight.

The content of the lecithin is preferably 10 to 75 parts by weight, morepreferably 11 to 60 parts by weight, still more preferably 20 to 55parts by weight, and most preferably 25 to 35 parts by weight when thetotal content of the emulsifier in the self-emulsifying composition is100 parts by weight.

The content of the lecithin is preferably 10 to 150 parts by weight,more preferably 20 to 120 parts by weight, and still more preferably 40to 90 parts by weight when the total content of the polyoxyethylenesorbitan fatty acid ester in the self-emulsifying composition is 100parts by weight. Most preferably, the content is 50 to 70 parts byweight.

In the present invention, the “polyhydric alcohol” is a polyol compoundhaving the structure of a straight chain or cyclic aliphatic hydrocarbonwherein two or more carbon atoms are each substituted with one hydroxygroup. Exemplary such polyhydric alcohols include divalent alcohols suchas ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butyleneglycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol,and pentamethylene glycol; trivalent alcohols such as glycerin,trimethylolpropane, and 1,2,6-hexane triol; and polyhydric alcoholpolymers such as diethylene glycol, dipropylene glycol triethyleneglycol, polyethylene glycol, polypropylene glycol, and polyglycerin, andthe preferred is propylene glycol or glycerin. The glycerin alsoincludes concentrated glycerin. The term “polyhydric alcohol” as used inthe present invention means all of such polyol compounds unlessotherwise noted.

Content of the polyhydric alcohol added in the self-emulsifyingcomposition of the present invention is such an amount that the capsuleis not deformed when the composition is filled in the capsule. Forexample, the content of the polyhydric alcohol in the composition ispreferably not more than 4% by weight when the total composition is 100%by weight. Content of the polyhydric alcohol in the composition ispreferably up to 4% by weight, more preferably up to 3% by weight, evenmore preferably up to 2% by weight, still more preferably up to 1% byweight, and most preferably 0% by weight.

Content of the ethanol in the self-emulsifying composition of thepresent invention is preferably such an amount that change in thequality is not induced during the encapsulation, distribution, orstorage, and denaturing of the capsule content is not induced. Also, theethanol content is preferably not exceed the daily experientiallyallowable medical dose. For example, the content of the ethanol in thecomposition is preferably not more the 4% by weight when the totalcomposition is 100% by weight. Content of the ethanol in the compositionis preferably up to 4% by weight, more preferably up to 3% by weight,even more preferably up to 2% by weight, still more preferably up to 1%by weight, and most preferably 0% by weight.

When the ethanol and the polyhydric alcohol are contained in theself-emulsifying composition, the total content of the ethanol and thepolyhydric alcohol in the composition is preferably not more than 4% byweight when the total amount of the composition is 100% by weight. Inthe preferred embodiment, the composition contains substantially noethanol and no polyhydric alcohol. Total content of the ethanol and thepolyhydric alcohol in the composition is preferably up to 4% by weight,more preferably up to 3% by weight, even more preferably up to 2% byweight, still more preferably up to 1% by weight, and most preferably 0%by weight.

Preferable ethanol concentration may be determined based on the ω3 PUFAconcentration of the self-emulsifying composition and the daily dose ofthe self-emulsifying composition. When the self-emulsifying compositionof the present invention is orally administered to each individual at adaily dose of 1800 mg in terms of ω3 PUFA, and a preparation containingthe ω3 PUFA, for example, at an amount of 75% by weight is prepared, theethanol dose will not exceed 3.26 mg which is daily maximum dosedescribed in the “Dictionary of Pharmaceutical Additives” when theethanol concentration is up to 0.135% by weight.

For the self-emulsifying composition of the present invention containingsuch ω3 PUFA and emulsifier as described above, a preferred embodimentis the combination containing 1) EPA-E and/or DHA-E, 2) water, 3) apolyoxyethylene sorbitan fatty acid ester as an emulsifier, and 4)lecithin. When the total amount of the self-emulsifying composition is100% by weight, the EPA-E and/or DHA-E 1) is 70 to 90% by weight, thewater 2) is 0.5 to 6% by weight, the emulsifier including thepolyoxyethylene sorbitan 3) is 1 to 29% by weight (excluding thelecithin), and the lecithin 4) is 3 to 40 parts by weight in relation to100 parts by weight of the EPA-E and/or DHA-E. Another preferredembodiment is the combination containing 1) EPA-E and/or DHA-E, 2)water, 3) a polyoxyethylene sorbitan fatty acid ester as the emulsifier,4) polyoxyl castor oil, and 5) lecithin. When the total amount of theself-emulsifying composition is 100% by weight, the EPA-E and/orDHA-E 1) is 70 to 90% by weight, the water 2) is 0.5 to 6% by weight,the emulsifier including the polyoxyethylene sorbitan 3) and thepolyoxyl castor oil (excluding the lecithin) is 1 to 29% by weight, andthe lecithin 4) is 3 to 40 parts by weight in relation to 100 parts byweight of the EPA-E and/or DHA-E. Another preferred embodiment is thecombination containing 1) at least one compound selected from ω3PUFAsand their pharmaceutically acceptable salts and esters, 2) water, 3) apolyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oilas the emulsifier, and 4) lecithin. When the total amount of theself-emulsifying composition is 100% by weight, the at least onecompound selected from ω3PUFAs and their pharmaceutically acceptablesalts and esters 1) is 70 to 90% by weight, the water 2) is 0.5 to 6% byweight, the emulsifier including the polyoxyethylene sorbitan fatty acidester and polyoxyethylene castor oil 3) is 5 to 24% by weight, with thepolyoxyethylene castor oil being up to 120 parts by weight in relationto 100 parts by weight of the polyoxyethylene sorbitan fatty acid ester,and the lecithin 4) is 3 to 40 parts by weight in relation to 100 partsby weight of the at least one compound selected from ω3PUFAs and theirpharmaceutically acceptable salts and esters.

The self-emulsifying composition of the present invention may beencapsulated in a capsule. The capsule selected may be a hard capsule ora soft capsule, and preferably, the capsule used is a soft capsule. Thesoft capsule is not particularly limited in shape, and preferably, thesoft capsule is a rotary die type soft capsule or a seamless capsule.

In the soft capsule of the present invention, the capsule film is notnecessarily limited for its composition, and exemplary main ingredientsinclude gelatin, carageenan, pectin, pullulan, sodium arginate, starch,hypromellose, hydroxypropyl cellulose, and other known ingredients. Thepreferred is gelatin, and the type of gelatin used is not particularlylimited. Exemplary gelatins include acid-treated gelatin, alkali-treatedgelatin, amphoteric gelatin, chemically modified gelatin, and otherknown gelatins, which may be used alone or in combination of two ormore. The gelatin used is preferably an acid-treated gelatin oralkali-treated gelatin. The source of the gelatin is not necessarilylimited, and the gelatin used may be the one from cattle bone, cattleskin, pig bone, pig skin, fish scale, or fish skin, and preferably, theone from cattle bone, cattle skin, pig bone, or pig skin.

The “gelatin” used may be the one normally used in the production of asoft capsule, for example, medical gelatin (gelatin and purifiedgelatin) defined in The Japanese Pharmacopoeia 16th edition. The gelatinmay also be a combination of two or more types, and the capsule film mayalso contain other components such as a plasticizing agent.

The “plasticizing agent” added to the capsule film may be the onenormally used in the production of a soft capsule, with preferredexamples including a polyhydric alcohol such as glycerin (for example,concentrated glycerin), ethylene glycol, polyethylene glycol, propyleneglycol, or polypropylene glycol, and a sugar alcohol such as sorbitol,mannitol, or xylitol. These plasticizing agents may be used incombination of two or more. Particularly preferred are glycerin andsorbitol. Also preferred is a combination of glycerin and sorbitol, andin this case, the glycerin and the sorbitol may be used at a weightratio in the range of 1:5 to 5:1, and more preferably 1:3 to 3:1.

In the soft capsule preparation, and in particular, in the seamlesscapsule of the present invention, the capsule film solution preferablycontains the gelatin and the plasticizing agent at a weight ratio in therange of 10:1 to 1:10, and more preferably of 10:1 to 1:1.

The weight ratio between the capsule film solution and the capsulecontent is typically 10:1 to 1:10, and preferably 3:1 to 1:10.

If desired, the capsule film may also contain various additives commonlyused in the capsule film. Exemplary such additives include amino acids,citric acid, glycerin, sorbitol, trehalose, and other plasticizingagents, antiseptic, dye, titanium oxide, and other colorants, andorganic acids.

The composition for the capsule film may be prepared by dissolvinggelatin, the plasticizing agent, and the optional additives in water atroom temperature or at an elevated temperature.

A capsulated self-emulsifying preparation having the self-emulsifyingcomposition of the present invention as its liquid content preferablyhas high hardness immediately after the production, and this hardness ispreferably maintained during the storage. Loss of the hardness isunfavorable in view of the quality because the loss of the hardness doesnot only result in the deformation but also fragileness and breakage ofthe capsule and bleeding of the content. Softening of the capsule can bedetected by measuring the hardness with a common hardness tester.

The capsulated self-emulsifying preparation of the present invention hasthe hardness immediately after the production of at least 18 kgf,preferably at least 20 kgf, and more preferably at least 22 kgf. It isdesirable that the hardness of the preparation does not substantiallydecrease, or not decrease by 6 kgf or more when the preparation isstored in a tightly sealed aluminum package at 40° C. for 1 weekcompared with the hardness immediately after the production. Preferably,the inventive preparation has a hardness of at least 10 kgf, morepreferably of at least 15 kgf, and even more preferably of at least 20kgf after the storage at 40° C. for 1 week.

With the hardness immediately after the production being assumed to be100%, at least 60%, preferably at least 70%, more preferably at least80%, even more preferably at least 85%, and most preferably at least 90%thereof is maintained after the storage in a tightly sealed aluminumpackage at 40° C. for 1 week.

The dose and dosage period of the ω3 PUFA used in the self-emulsifyingcomposition of the present invention are made sufficient for realizingthe intended action, and can be adequately adjusted depending on theadministration route, frequency of administration per day, seriousnessof the symptoms, body weight, age, and other factors.

In the case of oral administration, the composition is administered oneto three times a day at an EPA-E dose, for instance, per individual of10 to 12000 mg/day, 50 to 10000 mg/day, preferably 50 to 8000 mg, 100 to5000 mg/day, 100 to 4000 mg/day, more preferably 200 to 3000 mg/day, 300to 3000 mg/day, and still more preferably 500 to 3000 mg/day; oradministered one to three times a day at an EPA-E dose per individual of500 to 10000 mg/day, 500 to 4500 mg/day, 1500 to 4200 mg/day, andpreferably 1500 to 2400 mg/day, 3300 to 4200 mg/day, 7000 to 8100mg/day. The administration may be conducted one time at the entire doseor several times at divided doses as required. The composition may beadministered one to three times a day at an EPA-E dose per individual of1800 mg, 2000 mg, 2700 mg, 3000 mg, 3600 mg, 4000 mg, 6000 mg, 8000 mgor 10000 mg, with the administration being conducted one time at theentire dose or several times at divided doses as required. Tolerance ofthe daily dose or one divided dose as described above is ±5%. Thefrequency of administration per day is preferably one time a day or twoor three times a day. In the case of one time administration per day,one to ten capsules, preferably one to eight capsules, more preferablyone to six capsules, still more preferably one to four capsules, andeven more preferably one to three capsules as soft capsules eachcontaining 1000 mg of EPA-E, for instance, can be administered. Softcapsules each containing 100 mg of EPA-E may be combined with softcapsules each containing 500 mg of the ester so as to administer thecomposition at an EPA-E dose of 500 mg, 1500 mg, 2500 mg, 3500 mg, 4500mg or 5500 mg/administration. While administration of EPA-E during toafter meals is deemed preferable, and administration immediately aftermeals (within 30 minutes after meals) more preferable, because theabsorption of EPA-E is influenced by diet, the self-emulsifyingcomposition of the present invention has an excellent absorbabilityunder fasting, and therefore, it exerts the intended effects even whenadministered at a timing other than during, after or immediately aftermeals, for example, under fasting (at least 8 hours, and preferably atleast 10 hours after the last meal), before or immediately before meals,between meals, or at bedtime; when administered to patients with reducedabsorption ability of the intestinal tract (for example, elderly,patients of intestinal disease, patients after intestinal surgery,terminal cancer patients, or patients taking a lipase inhibitor); orwhen administered at a reduced dose.

The self-emulsifying composition of the present invention is preferablycharacterized in that the time until the maximum plasma ω3 PUFAconcentration is attained after the oral administration is comparable toor shorter than that found for the ω3 PUFA stock solution. Otherwise,the inventive composition is preferably characterized in that themaximum plasma ω3 PUFA concentration is higher than that found for theω3 PUFA stock solution (a composition containing the ω3 PUFA in the sameamount as the self-emulsifying composition of the present invention butnot containing the emulsifier and the like). In addition, the inventivecomposition is preferably characterized in that the plasma ω3 PUFAconcentration two hours after the administration, the area under theplasma ω3 PUFA concentration vs time curve from zero to two hours afterthe administration, and/or the area under the plasma ω3 PUFAconcentration vs time curve from zero to 72 hours after theadministration is comparable to or higher than that found for the ω3PUFA stock solution. More preferably, the self-emulsifying compositionof the present invention is characterized in that the time until themaximum plasma ω3 PUFA concentration is attained is short, such maximumconcentration is high, and both the plasma concentration two hours afterthe administration and the area under the plasma ω3 PUFA concentrationvs time curve from zero to two hours and/or from zero to 72 hours afterthe administration are high as compared with those for the ω3 PUFA stocksolution, respectively. Most preferably, the above parameters of theself-emulsifying composition of the present invention are higher thanthose obtained in the case when the ω3 PUFA stock solution isadministered immediately after meals.

Such pharmacokinetics as above can be confirmed with dogs, monkeys orother animals, and preferably by examination on humans.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to male beagles as fasted for at least 18hours at an ω3 PUFA dose per individual of 600 mg, the maximum plasma ω3PUFA concentration is, for instance, preferably at least 50 μg/mL, morepreferably at least 60 μg/mL, and even more preferably at least 70μg/mL, as calculated with correction by subtraction of the plasma ω3PUFA concentration before the administration of the composition. Thearea under the plasma ω3 PUFA concentration vs time curve from zero totwo hours after the administration is preferably at least 50 μg·hr/mL,more preferably at least 60 μg·hr/mL, and even more preferably at least70 μg·hr/mL. The combination of the ranges of the maximum plasma ω3 PUFAconcentration and the area under the plasma ω3 PUFA concentration vstime curve is preferably a combination of the range of at least 50 μg/mLand the range of at least 50 μg·hr/mL, more preferably a combination ofthe range of at least 60 μg/mL and the range of at least 60 μg·hr/mL,and even more preferably a combination of the range of at least 70 μg/mLand the range of at least 70 μg·hr/mL.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to male crab-eating macaques as fasted forat least 12 hours at an ω3 PUFA dose of 45 mg/kg body weight, themaximum plasma ω3 PUFA concentration is preferably at least 50 μg/mL,and more preferably 70 μg/mL, as calculated with correction bysubtraction of the plasma ω3 PUFA concentration before theadministration of the composition. The area under the plasma ω3 PUFAconcentration vs time curve from zero to 12 hours after theadministration is preferably at least 400 μg·hr/mL, and more preferably500 μg/mL. The combination of the ranges of the maximum plasma ω3 PUFAconcentration and the area under the plasma ω3 PUFA concentration vstime curve as above is preferably a combination of the range of at least50 μg/ml, and the range of at least 400 μg·hr/mL, and more preferably acombination of the range of at least 70 μg/mL and the range of at least500 μg·hr/mL.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans before meals, immediately aftermeals or after meals at an ω3 PUFA or EPA dose per individual of 500 mgto 1800 mg, the maximum plasma ω3 PUFA concentration is preferably atleast 50 μg/mL, more preferably at least 100 μg/mL, still morepreferably at least 150 μg/mL, even more preferably at least 180 μg/mL,and most preferably at least 350 μg/mL, as calculated with correction bysubtraction of the plasma ω3 PUFA concentration before theadministration of the composition. Alternatively, the maximum plasma ω3PUFA concentration is preferably 10 to 1000 μg/mL, more preferably 20 to700 μg/mL, still more preferably 40 to 600 μg/mL, even more preferably50 to 500 μg/mL, and most preferably 60 to 480 μg/mL. The plasma ω3 PUFAconcentration 24 hours after the administration is preferably 5 to 100μg/mL, more preferably 10 to 90 μg/mL, still more preferably 15 to 85μg/mL, still more preferably 20 to 80 μg/mL, and most preferably 30 to70 μg/mL. The area under the plasma ω3 PUFA concentration vs time curvefrom zero to 72 hours after the administration is preferably at least500 μg·hr/mL, more preferably at least 800 μg·hr/mL, still morepreferably at least 1000 μg·hr/mL, even more preferably at least 1500μg·hr/mL, and most preferably at least 1800 μg·hr/mL. Alternatively, thearea under the plasma ω3 PUFA concentration vs time curve as above ispreferably 500 to 9000 μg·hr/mL, more preferably 600 to 8000 μg·hr/mL,still more preferably 700 to 7000 μg·hr/mL, even more preferably 800 to5000 μg·hr/mL, and most preferably 1500 to 4500 μg·hr/mL. The time untilthe maximum plasma ω3 PUFA concentration is attained is preferably up to6 hours, more preferably up to 5.5 hours, still more preferably up to 5hours, even more preferably up to 4 hours, and most preferably less thanone hour. Alternatively, the time until the maximum plasma ω3 PUFAconcentration is attained is preferably 0.5 to 10 hours, more preferably1 to 8 hours, still more preferably 1.5 to 7 hours, even more preferably2 to 7 hours, and most preferably 3 to 6 hours. The plasma ω3 PUFAelimination half-life is preferably at least 10 hours, more preferablyat least 20 hours, still more preferably at least 30 hours, even morepreferably at least 40 hours, and most preferably at least 50 hours.Alternatively, the plasma ω3 PUFA elimination half-life is preferably 0to 150 hours, more preferably 10 to 120 hours, still more preferably 30to 100 hours, even more preferably 25 to 75 hours, and most preferably25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans before meals, immediately aftermeals or after meals at an ω3 PUFA or EPA dose per individual of 1500 mgto 4200 mg, the maximum plasma ω3 PUFA concentration is preferably atleast 50 μg/mL, more preferably at least 60 μg/mL, still more preferablyat least 70 μg/mL, even more preferably at least 100 μg/mL, and mostpreferably at least 150 μg/mL, as calculated with correction bysubtraction of the plasma ω3 PUFA concentration before theadministration of the composition. Alternatively, the maximum plasma ω3PUFA concentration is preferably 10 to 1000 μg/mL, more preferably 20 to600 μg/mL, still more preferably 40 to 400 μg/mL, even more preferably50 to 300 μg/mL, and most preferably 60 to 250 μg/mL. The plasma ω3 PUFAconcentration 24 hours after the administration is preferably 5 to 100μg/mL, more preferably 10 to 90 μg/mL, still more preferably 12 to 60μg/mL, still more preferably 15 to 50 μg/mL, and most preferably 20 to45 μg/mL. The area under the plasma ω3 PUFA concentration vs time curvefrom zero to 72 hours after the administration is preferably at least500 μg·hr/mL, more preferably at least 800 μg·hr/mL, still morepreferably at least 1000 μg·hr/mL, even more preferably at least 1500μg·hr/mL, and most preferably at least 2000 μg·hr/mL. Alternatively, thearea under the plasma ω3 PUFA concentration vs time curve as above ispreferably 500 to 6000 μg·hr/mL, more preferably 600 to 5000 μg·hr/mL,still more preferably 700 to 4000 μg·hr/mL, even more preferably 800 to3500 μg·hr/mL, and most preferably 1000 to 3000 μg·hr/mL. The time untilthe maximum plasma ω3 PUFA concentration is attained is preferably up to6 hours, more preferably up to 5.5 hours, still more preferably up to 5hours, even more preferably up to 4 hours, and most preferably less thanone hour. Alternatively, the time until the maximum plasma ω3 PUFAconcentration is attained is preferably 0.5 to 10 hours, more preferably1 to 8 hours, still more preferably 1.5 to 7 hours, even more preferably2 to 7 hours, and most preferably 3 to 6 hours. The plasma ω3 PUFAelimination half-life is preferably at least 10 hours, more preferablyat least 20 hours, still more preferably at least 30 hours, even morepreferably at least 40 hours, and most preferably at least 50 hours.Alternatively, the plasma ω3 PUFA elimination half-life is preferably 0to 150 hours, more preferably 10 to 120 hours, still more preferably 30to 100 hours, even more preferably 25 to 75 hours, and most preferably25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans before meals, immediately aftermeals or after meals at an ω3 PUFA or EPA dose per individual of 1500 mgto 2400 mg (for example, 2000 mg), the maximum plasma ω3 PUFAconcentration is preferably at least 40 μg/mL, more preferably at least50 μg/mL, still more preferably at least 60 μg/mL, even more preferablyat least 65 μg/mL, and most preferably at least 100 μg/mL, as calculatedwith correction by subtraction of the plasma ω3 PUFA concentrationbefore the administration of the composition. Alternatively, the maximumplasma ω3 PUFA concentration is preferably 10 to 1000 μg/mL, morepreferably 20 to 500 μg/mL, still more preferably 40 to 300 μg/mL, evenmore preferably 50 to 150 μg/mL, and most preferably 60 to 120 μg/mL.The plasma concentration 24 hours after the administration is preferably5 to 70 μg/mL, more preferably 10 to 60 μg/mL, still more preferably 15to 50 μg/mL, still more preferably 18 to 40 μg/mL, and most preferably20 to 35 μg/mL. The area under the plasma ω3 PUFA concentration vs timecurve from zero to 72 hours after the administration is preferably atleast 500 μg·hr/mL, more preferably at least 800 μg·hr/mL, still morepreferably at least 1000 μg·hr/mL, even more preferably at least 1200μg·hr/mL, and most preferably at least 1500 μg·hr/mL. Alternatively, thearea under the plasma ω3 PUFA concentration vs time curve as above ispreferably 500 to 5000 μg·hr/mL, more preferably 600 to 4000 μg·hr/mL,still more preferably 700 to 3000 μg·hr/mL, even more preferably 800 to2500 μg·hr/mL, and most preferably 1000 to 2100 μg·hr/mL. The time untilthe maximum plasma ω3 PUFA concentration is attained is preferably up to6 hours, more preferably up to 5.5 hours, still more preferably up to 5hours, even more preferably up to 4 hours, and most preferably less thanone hour. Alternatively, the time until the maximum plasma ω3 PUFAconcentration is attained is preferably 0.5 to 10 hours, more preferably1 to 8 hours, still more preferably 1.5 to 7 hours, even more preferably2 to 7 hours, and most preferably 3 to 6 hours. The plasma ω3 PUFAelimination half-life is preferably at least 10 hours, more preferablyat least 20 hours, still more preferably at least 30 hours, even morepreferably at least 40 hours, and most preferably at least 50 hours.Alternatively, the plasma ω3 PUFA elimination half-life is preferably 0to 150 hours, more preferably 10 to 120 hours, still more preferably 30to 100 hours, even more preferably 25 to 75 hours, and most preferably25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans before meals, immediately aftermeals or after meals at an ω3 PUFA or EPA dose per individual of 3300 mgto 4200 mg (for example, 4000 mg), the maximum plasma ω3 PUFAconcentration is preferably at least 50 μg/mL, more preferably at least100 μg/mL, still more preferably at least 150 μg/mL, even morepreferably at least 160 μg/mL, and most preferably at least 180 μg/mL,as calculated with correction by subtraction of the plasma ω3 PUFAconcentration before the administration of the composition.Alternatively, the maximum plasma ω3 PUFA concentration is preferably 10to 1000 μg/mL, more preferably 20 to 500 μg/mL, still more preferably 50to 400 μg/mL, even more preferably 100 to 300 μg/mL, and most preferably150 to 200 μg/mL. The plasma ω3 PUFA concentration 24 hours after theadministration is preferably 10 to 80 μg/mL, more preferably 20 to 60μg/mL, still more preferably 25 to 55 μg/mL, still more preferably 30 to50 μg/mL, and most preferably 35 to 45 μg/mL. The area under the plasmaω3 PUFA concentration vs time curve from zero to 72 hours after theadministration is preferably at least 500 μg·hr/mL, more preferably atleast 1000 μg·hr/mL, still more preferably at least 1500 μg·hr/mL, evenmore preferably at least 2000 μg·hr/mL, and most preferably at least2500 μg·hr/mL. Alternatively, the area under the plasma ω3 PUFAconcentration vs time curve as above is preferably 500 to 5000 μg·hr/mL,more preferably 1000 to 4700 μg·hr/mL, still more preferably 1500 to4500 μg·hr/mL, even more preferably 2000 to 4000 μg·hr/mL, and mostpreferably 2500 to 3500 μg·hr/mL. The time until the maximum plasma ω3PUFA concentration is attained is preferably up to 6 hours, morepreferably up to 5.5 hours, still more preferably up to 5 hours, evenmore preferably up to 4 hours, and most preferably less than one hour.Alternatively, the time until the maximum plasma ω3 PUFA concentrationis attained is preferably 0.5 to 10 hours, more preferably 1 to 8 hours,still more preferably 1.5 to 7 hours, even more preferably 2 to 7 hours,and most preferably 3 to 6 hours. The plasma elimination half-life ispreferably at least 10 hours, more preferably at least 20 hours, stillmore preferably at least 30 hours, even more preferably at least 40hours, and most preferably at least 50 hours. Alternatively, the plasmaelimination half-life is preferably 0 to 150 hours, more preferably 10to 120 hours, still more preferably 30 to 100 hours, even morepreferably 25 to 75 hours, and most preferably 25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans before meals, immediately aftermeals or after meals at an ω3 PUFA or EPA dose per individual of 7000 mgto 8500 mg (for example, 8000 mg), the maximum plasma ω3 PUFAconcentration is preferably at least 100 μg/mL, more preferably at least200 μg/mL, still more preferably at least 300 μg/mL, even morepreferably at least 350 μg/mL, and most preferably at least 400 μg/mL,as calculated with correction by subtraction of the plasma ω3 PUFAconcentration before the administration of the composition.Alternatively, the maximum plasma ω3 PUFA concentration is preferably100 to 1000 μg/mL, more preferably 200 to 800 μg/mL, still morepreferably 300 to 600 μg/mL, even more preferably 300 to 500 μg/mL, andmost preferably 350 to 500 μg/mL. The plasma ω3 PUFA concentration 24hours after the administration is preferably 10 to 100 μg/mL, morepreferably 30 to 90 μg/mL, still more preferably 50 to 85 μg/mL, stillmore preferably 55 to 85 μg/mL, and most preferably 65 to 80 μg/mL. Thearea under the plasma ω3 PUFA concentration vs time curve from zero to72 hours after the administration is preferably at least 1000 μg·hr/mL,more preferably at least 2000 μg·hr/mL, still more preferably at least3000 μg·hr/mL, even more preferably at least 4000 μg·hr/mL, and mostpreferably at least 5000 μg·hr/mL. Alternatively, the area under theplasma ω3 PUFA concentration vs time curve as above is preferably 1000to 10000 μg·hr/mL, more preferably 2000 to 8000 μg·hr/mL, still morepreferably 3000 to 7000 μg·hr/mL, even more preferably 3500 to 6500μg·hr/mL, and most preferably 4000 to 6500 μg·hr/mL. The time until themaximum plasma ω3 PUFA concentration is attained is preferably up to 6hours, more preferably up to 5.5 hours, still more preferably up to 5hours, even more preferably up to 4 hours, and most preferably less thanone hour. Alternatively, the time until the maximum plasma ω3 PUFAconcentration is attained is preferably 0.5 to 10 hours, more preferably1 to 8 hours, still more preferably 1.5 to 7 hours, even more preferably2 to 7 hours, and most preferably 3 to 6 hours. The plasma ω3 PUFAelimination half-life is preferably at least 10 hours, more preferablyat least 20 hours, still more preferably at least 30 hours, even morepreferably at least 40 hours, and most preferably at least 50 hours.Alternatively, the plasma ω3 PUFA elimination half-life is preferably 0to 150 hours, more preferably 10 to 120 hours, still more preferably 30to 100 hours, even more preferably 25 to 75 hours, and most preferably25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans under fasting, before meals,immediately after meals or after meals at an ω3 PUFA or EPA dose perindividual of 1800 mg, the maximum plasma ω3 PUFA concentration ispreferably at least 50 μg/mL, more preferably at least 100 μg/mL, stillmore preferably at least 150 μg/mL, even more preferably at least 200μg/mL, and most preferably at least 300 μg/mL, as calculated withcorrection by subtraction of the plasma ω3 PUFA concentration before theadministration of the composition. Alternatively, the maximum plasma ω3PUFA concentration is preferably 10 to 1000 μg/mL, more preferably 20 to500 μg/mL, still more preferably 40 to 300 μg/mL, even more preferably50 to 150 μg/mL, and most preferably 50 to 100 μg/mL. Alternatively, themaximum plasma ω3 PUFA concentration is preferably at least 50 μg/mL,more preferably at least 60 μg/mL, still more preferably at least 65μg/mL, even more preferably at least 80 μg/mL, and most preferably atleast 100 μg/mL. Alternatively, the maximum plasma ω3 PUFA concentrationis preferably 10 to 1000 μg/mL, more preferably 20 to 500 μg/mL, stillmore preferably 40 to 300 μg/mL, even more preferably 50 to 150 μg/mL,and most preferably 60 to 120 μg/mL. The plasma ω3 PUFA concentration 24hours after the administration is preferably 5 to 70 μg/mL, morepreferably 10 to 60 μg/mL, still more preferably 13 to 50 μg/mL, stillmore preferably 15 to 40 μg/mL, and most preferably 18 to 30 μg/mL. Thearea under the plasma ω3 PUFA concentration vs time curve from zero to72 hours after the administration is preferably at least 500 μg·hr/mL,more preferably at least 1000 μg·hr/mL, still more preferably at least1500 μg·hr/mL, even more preferably at least 2000 μg·hr/mL, and mostpreferably at least 3000 μg·hr/mL. Alternatively, the area under theplasma ω3 PUFA concentration vs time curve as above is preferably 500 to4500 μg·hr/mL, more preferably 600 to 3000 μg·hr/mL, still morepreferably 700 to 2500 μg·hr/mL, even more preferably 800 to 2000μg·hr/mL, and most preferably 1000 to 1500 μg·hr/mL. Alternatively, thearea under the plasma ω3 PUFA concentration vs time curve from zero to72 hours after the administration is preferably at least 500 μg·hr/mL,more preferably at least 800 μg·hr/mL, still more preferably at least1000 μg·hr/mL, even more preferably at least 1500 μg·hr/mL, and mostpreferably at least 1800 μg·hr/mL. Alternatively, the area under theplasma ω3 PUFA concentration vs time curve as above is preferably 500 to4500 μg·hr/mL, more preferably 600 to 3000 μg·hr/mL, still morepreferably 700 to 2500 μg·hr/mL, even more preferably 800 to 2200μg·hr/mL, and most preferably 1000 to 2100 μg·hr/mL. The time until themaximum plasma ω3 PUFA concentration is attained is preferably up to 6hours, more preferably up to 5 hours, still more preferably up to 3hours, even more preferably up to 1 hour, and most preferably less thanone hour. Alternatively, the time until the maximum plasma ω3 PUFAconcentration is attained is preferably 0.5 to 10 hours, more preferably1 to 8 hours, still more preferably 1.5 to 7 hours, even more preferably2 to 5 hours, and most preferably 2.5 to 4 hours. Alternatively, thetime until the maximum plasma ω3 PUFA concentration is attained ispreferably up to 6 hours, more preferably up to 5.5 hours, still morepreferably up to 5 hours, even more preferably up to 4 hours, and mostpreferably less than one hour. Alternatively, the time until the maximumplasma ω3 PUFA concentration is attained is preferably 0.5 to 10 hours,more preferably 1 to 8 hours, still more preferably 1.5 to 7 hours, evenmore preferably 2 to 7 hours, and most preferably 3 to 6 hours. Theplasma ω3 PUFA elimination half-life is preferably at least 10 hours,more preferably at least 20 hours, still more preferably at least 30hours, even more preferably at least 40 hours, and most preferably atleast 50 hours. Alternatively, the plasma ω3 PUFA elimination half-lifeis preferably 0 to 150 hours, more preferably 10 to 120 hours, stillmore preferably 30 to 100 hours, even more preferably 25 to 75 hours,and most preferably 25 to 50 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans at such a timing as underfasting, before meals, immediately after meals or after meals at an ω3PUFA or EPA dose of 3600 mg, the maximum plasma ω3 PUFA concentration ispreferably at least 50 μg/mL, more preferably at least 100 μg/mL, stillmore preferably at least 150 μg/mL, even more preferably at least 200μg/mL, and most preferably at least 300 μg/mL, as calculated withcorrection by subtraction of the plasma ω3 PUFA concentration before theadministration of the composition. Alternatively, the maximum plasma ω3PUFA concentration is preferably at least 50 μg/mL, more preferably atleast 100 μg/mL, still more preferably at least 150 μg/mL, even morepreferably at least 160 μg/mL, and most preferably at least 180 μg/mL.Alternatively, the maximum plasma ω3 PUFA concentration is preferably 10to 1000 μg/mL, more preferably 20 to 500 μg/mL, still more preferably 50to 400 μg/mL, even more preferably 100 to 300 μg/mL, and most preferably150 to 200 μg/mL. The plasma ω3 PUFA concentration 24 hours after theadministration is preferably 10 to 80 μg/mL, more preferably 20 to 60μg/mL, still more preferably 25 to 50 μg/mL, still more preferably 30 to45 μg/mL, and most preferably 35 to 40 μg/mL. The area under the plasmaω3 PUFA concentration vs time curve from zero to 72 hours after theadministration is preferably at least 500 μg·hr/mL, more preferably atleast 1000 μg·hr/mL, still more preferably at least 1500 μg·hr/mL, evenmore preferably at least 2000 μg·hr/mL, and most preferably at least2500 or 3000 μg·hr/mL. Alternatively, the area under the plasma ω3 PUFAconcentration vs time curve as above is preferably 500 to 5000 μg·hr/mL,more preferably 1000 to 4700 μg·hr/mL, still more preferably 1500 to4500 μg·hr/mL, even more preferably 2000 to 4000 μg·hr/mL, and mostpreferably 2500 to 3500 μg·hr/mL. The time until the maximum plasma ω3PUFA concentration is attained is preferably up to 6 hours, morepreferably up to 5 hours, still more preferably up to 3 hours, even morepreferably up to 1 hour, and most preferably less than one hour.Alternatively, the time until the maximum plasma ω3 PUFA concentrationis attained is preferably up to 6 hours, more preferably up to 5.5hours, still more preferably up to 5 hours, even more preferably up to4.5 hours, and most preferably less than one hour. Alternatively, thetime until the maximum plasma ω3 PUFA concentration is attained ispreferably 0.5 to 10 hours, more preferably 1 to 8 hours, still morepreferably 1.5 to 7 hours, even more preferably 2 to 6 hours, and mostpreferably 3.5 to 5.5 hours or 3 to 5 hours. The plasma ω3 PUFAelimination half-life is preferably at least 10 hours, more preferablyat least 20 hours, still more preferably at least 30 hours, even morepreferably at least 40 hours, and most preferably at least 50 hours.Alternatively, the plasma ω3 PUFA elimination half-life is preferably 0to 150 hours, more preferably 10 to 120 hours, still more preferably 30to 100 hours, even more preferably 25 to 75 hours, and most preferably25 to 50 hours.

In the case of a pharmacokinetic study with humans, the above-mentionednumerical ranges may also be replaced by those mentioned below. To bemore specific: In a study conducted by orally administering theself-emulsifying composition at such a timing as under fasting, beforemeals, immediately after meals or after meals and at an ω3 PUFA or EPAdose per individual of 1800 mg, the maximum plasma ω3 PUFA concentrationas calculated with correction by subtraction of the plasma ω3 PUFAconcentration before the administration of the composition is notparticularly limited, while it may be specified to be: 10 to 150, 20 to160, 30 to 170, 40 to 180, 50 to 190, 60 to 200, 10 to 50, 50 to 100,100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400,400 to 450, 450 to 500, 500 to 600, 600 to 700, 700 to 800, 800 to 900,900 to 1000, 10 to 30, 20 to 40, 30 to 50, 40 to 60, 50 to 70, 60 to 80,70 to 90, 80 to 100, 90 to 110, 100 to 120, 110 to 130, 120 to 140, 130to 150, 140 to 160, 150 to 170, 160 to 180, 170 to 190, 180 to 200, 190to 210, 200 to 220, 220 to 240, 240 to 260, 260 to 280, 280 to 300, 10to 20, 15 to 25, 20 to 30, 25 to 35, 30 to 40, 35 to 45, 40 to 50, 45 to55, 50 to 55, 53 to 58, 55 to 60, 58 to 63, 60 to 65, 63 to 68, 65 to70, 68 to 73, 70 to 75, 73 to 78, 75 to 80, 78 to 83, 80 to 85, 83 to88, 85 to 90, 88 to 93, 90 to 95, 93 to 98, 95 to 100, 98 to 103, 100 to105, 103 to 108, 105 to 110, 108 to 113, 110 to 115, 113 to 118, 115 to120, 118 to 123, 120 to 125, 123 to 128, 125 to 130, 128 to 133, 130 to135, 133 to 138, 135 to 140, 138 to 143, 140 to 145, 143 to 148, 145 to150, 150 to 160, 155 to 165, 160 to 170, 165 to 175, 170 to 180, 175 to185, 180 to 190, 185 to 195, 190 to 200, 195 to 205, 200 to 210, 205 to215, 210 to 220, 215 to 225, 220 to 230, 225 to 235, 230 to 240, 235 to245, or 240 to 250 μg/ml. In a study conducted by administering theself-emulsifying composition at such a timing as under fasting, beforemeals, immediately after meals or after meals and at an ω3 PUFA or EPAdose per individual of 3600 mg, the maximum plasma ω3 PUFA concentrationmay be specified to be: 10 to 200, 30 to 220, 50 to 240, 70 to 260, 90to 280, 110 to 300, 130 to 320, 150 to 350, 10 to 50, 50 to 100, 100 to150, 150 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400, 400 to450, 450 to 500, 500 to 600, 600 to 700, 700 to 800, 800 to 900, 900 to1000, 10 to 30, 20 to 40, 30 to 50, 40 to 60, 50 to 70, 60 to 80, 70 to90, 80 to 100, 90 to 110, 100 to 120, 110 to 130, 120 to 140, 130 to150, 140 to 160, 150 to 170, 160 to 180, 170 to 190, 180 to 200, 190 to210, 200 to 220, 220 to 240, 240 to 260, 260 to 280, 280 to 300, 10 to20, 15 to 25, 20 to 30, 25 to 35, 30 to 40, 35 to 45, 40 to 50, 45 to55, 50 to 55, 53 to 58, 55 to 60, 58 to 63, 60 to 65, 63 to 68, 65 to70, 68 to 73, 70 to 75, 73 to 78, 75 to 80, 78 to 83, 80 to 85, 83 to88, 85 to 90, 88 to 93, 90 to 95, 93 to 98, 95 to 100, 98 to 103, 100 to105, 103 to 108, 105 to 110, 108 to 113, 110 to 115, 113 to 118, 115 to120, 118 to 123, 120 to 125, 123 to 128, 125 to 130, 128 to 133, 130 to135, 133 to 138, 135 to 140, 138 to 143, 140 to 145, 143 to 148, 145 to150, 150 to 160, 155 to 165, 160 to 170, 165 to 175, 170 to 180, 175 to185, 180 to 190, 185 to 195, 190 to 200, 195 to 205, 200 to 210, 205 to215, 210 to 220, 215 to 225, 220 to 230, 225 to 235, 230 to 240, 235 to245, or 240 to 250 μg/ml.

The area under the plasma ω3 PUFA concentration vs time curve from zeroto 72 hours after the administration in a study conducted byadministering the self-emulsifying composition at such a timing as underfasting, before meals, immediately after meals or after meals and at anω3 PUFA or EPA dose per individual of 1800 mg may be specified to be:500 to 2000, 700 to 2200, 900 to 2400, 1100 to 2600, 500 to 1500, 1000to 2000, 1500 to 2500, 2000 to 3000, 2500 to 3500, 3000 to 4000, 500 to1000, 750 to 1250, 1000 to 1500, 1250 to 1750, 1500 to 2000, 1750 to2250, 2000 to 2500, 2250 to 2750, 2500 to 3000, 2750 to 3250, 3000 to3500, 3250 to 3750, 3500 to 4000, 3750 to 4250, 4000 to 4500, 4250 to4750, 4500 to 5000, 500 to 700, 600 to 800, 700 to 900, 800 to 1000, 900to 1100, 1000 to 1200, 1100 to 1300, 1200 to 1400, 1300 to 1500, 1400 to1600, 1500 to 1700, 1600 to 1800, 1700 to 1900, 1800 to 2000, 1900 to2100, 2000 to 2200, 2100 to 2300, 2200 to 2400, 2300 to 2500, 2400 to2600, 2500 to 2700, 2600 to 2800, 2700 to 2900, 2800 to 3000, 2900 to3100, 3000 to 3200, 3100 to 3300, 3200 to 3400, 3300 to 3500, 3400 to3600, 3500 to 3700, 3600 to 3800, 3700 to 3900, 3800 to 4000, 3900 to4100, 4000 to 4200, 4100 to 4300, 4200 to 4400, 4300 to 4500, 500 to600, 550 to 650, 600 to 700, 650 to 750, 700 to 800, 750 to 850, 800 to900, 850 to 950, 900 to 1000, 950 to 1050, 1000 to 1100, 1050 to 1150,1100 to 1200, 1150 to 1250, 1200 to 1300, 1250 to 1350, 1300 to 1400,1350 to 1450, 1400 to 1500, 1450 to 1550, 1500 to 1600, 1550 to 1650,1600 to 1700, 1650 to 1750, 1700 to 1800, 1750 to 1850, 1800 to 1900,1850 to 1950, 1900 to 2000, 1950 to 2050, 2000 to 2100, 2050 to 2150,2100 to 2200, 2150 to 2250, 2200 to 2300, 2250 to 2350, 2300 to 2400,2350 to 2450, 2400 to 2500, 2450 to 2550, 2500 to 2600, 2550 to 2650,2600 to 2700, 2650 to 2750, 2700 to 2800, 2750 to 2850, 2800 to 2900,2850 to 2950, 2900 to 3000, 2950 to 3050, 3000 to 3100, 3150 to 3250,3200 to 3300, 3250 to 3350, 3300 to 3400, 3350 to 3450, 3400 to 3500,3500 to 3600, 3600 to 3700, 3700 to 3800, 3800 to 3900, 3900 to 4000,4000 to 4100, 4100 to 4200, 4200 to 4300, 4300 to 4400, or 4400 to 4500μg·hr/mL. In a study conducted by administering the self-emulsifyingcomposition at such a timing as under fasting, before meals, immediatelyafter meals or after meals and at an ω3 PUFA or EPA dose per individualof 3600 mg, the area under the plasma ω3 PUFA concentration vs timecurve as above may be specified to be: 1500 to 3000, 1800 to 3300, 2100to 3600, 2400 to 3900, 500 to 1500, 1000 to 2000, 1500 to 2500, 2000 to3000, 2500 to 3500, 3000 to 4000, 500 to 1000, 750 to 1250, 1000 to1500, 1250 to 1750, 1500 to 2000, 1750 to 2250, 2000 to 2500, 2250 to2750, 2500 to 3000, 2750 to 3250, 3000 to 3500, 3250 to 3750, 3500 to4000, 3750 to 4250, 4000 to 4500, 4250 to 4750, 4500 to 5000, 500 to700, 600 to 800, 700 to 900, 800 to 1000, 900 to 1100, 1000 to 1200,1100 to 1300, 1200 to 1400, 1300 to 1500, 1400 to 1600, 1500 to 1700,1600 to 1800, 1700 to 1900, 1800 to 2000, 1900 to 2100, 2000 to 2200,2100 to 2300, 2200 to 2400, 2300 to 2500, 2400 to 2600, 2500 to 2700,2600 to 2800, 2700 to 2900, 2800 to 3000, 2900 to 3100, 3000 to 3200,3100 to 3300, 3200 to 3400, 3300 to 3500, 3400 to 3600, 3500 to 3700,3600 to 3800, 3700 to 3900, 3800 to 4000, 3900 to 4100, 4000 to 4200,4100 to 4300, 4200 to 4400, 4300 to 4500, 500 to 600, 550 to 650, 600 to700, 650 to 750, 700 to 800, 750 to 850, 800 to 900, 850 to 950, 900 to1000, 950 to 1050, 1000 to 1100, 1050 to 1150, 1100 to 1200, 1150 to1250, 1200 to 1300, 1250 to 1350, 1300 to 1400, 1350 to 1450, 1400 to1500, 1450 to 1550, 1500 to 1600, 1550 to 1650, 1600 to 1700, 1650 to1750, 1700 to 1800, 1750 to 1850, 1800 to 1900, 1850 to 1950, 1900 to2000, 1950 to 2050, 2000 to 2100, 2050 to 2150, 2100 to 2200, 2150 to2250, 2200 to 2300, 2250 to 2350, 2300 to 2400, 2350 to 2450, 2400 to2500, 2450 to 2550, 2500 to 2600, 2550 to 2650, 2600 to 2700, 2650 to2750, 2700 to 2800, 2750 to 2850, 2800 to 2900, 2850 to 2950, 2900 to3000, 2950 to 3050, 3000 to 3100, 3150 to 3250, 3200 to 3300, 3250 to3350, 3300 to 3400, 3350 to 3450, 3400 to 3500, 3500 to 3600, 3600 to3700, 3700 to 3800, 3800 to 3900, 3900 to 4000, 4000 to 4100, 4100 to4200, 4200 to 4300, 4300 to 4400, or 4400 to 4500 μg·hr/mL.

The time until the maximum plasma ω3 PUFA concentration is attained in astudy conducted by administering the self-emulsifying composition atsuch a timing as under fasting, before meals, immediately after meals orafter meals and at an ω3 PUFA or EPA dose per individual of 1800 mg to3600 mg or of 1800 mg to 4000 mg may be specified to be: 0 to 5.5, 1 to6, 1.5 to 6.5, 2 to 7, 0 to 2, 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6to 8, 7 to 9, 8 to 10, 0 to 1, 0.5 to 1.5, 1 to 2, 1.5 to 2.5, 2 to 3,2.5 to 3.5, 3 to 4, 3.5 to 4.5, 4 to 5, 4.5 to 5.5, 5 to 6, 5.5 to 6.5,6 to 7, 6.5 to 7.5, 7 to 8, 7.5 to 8.5, 8 to 9, 8.5 to 9.5, 9 to 10, 0to 0.5, 0.3 to 0.8, 0.5 to 1, 0.8 to 1.3, 1 to 1.5, 1.3 to 1.8, 1.5 to2, 1.8 to 2.3, 2 to 2.5, 2.3 to 2.8, 2.5 to 3, 2.8 to 3.3, 3 to 3.5, 3.3to 3.8, 3.5 to 4, 3.8 to 4.3, 4 to 4.5, 4.3 to 4.8, 4.5 to 5, 4.8 to5.3, 5 to 5.5, 5.3 to 5.8, 5.5 to 6, 5.8 to 6.3, 6 to 6.5, 6.3 to 6.8,6.5 to 7, 6.8 to 7.3, 7 to 7.5, 7.3 to 7.8, 7.5 to 8, 7.8 to 8.3, 8 to8.5, 8.3 to 8.8, 8.5 to 9, 8.8 to 9.3, 9 to 9.5, 9.3 to 9.8, or 9.5 to10 hours.

The plasma ω3 PUFA elimination half-life in a study conducted byadministering the self-emulsifying composition at such a timing as underfasting, before meals, immediately after meals or after meals and at anω3 PUFA or EPA dose per individual of 1800 mg to 3600 mg or of 1800 mgto 4000 mg may be specified to be: 0 to 70, 10 to 80, 20 to 90, 30 to100, 40 to 110, 0 to 50, 25 to 75, 50 to 100, 75 to 125, 100 to 150, 125to 175, 150 to 200, 0 to 20, 10 to 30, 20 to 40, 30 to 50, 40 to 60, 50to 70, 60 to 80, 70 to 90, 80 to 100, 90 to 110, 100 to 120, 110 to 130,120 to 140, 130 to 150, 0 to 10, 5 to 15, 10 to 20, 15 to 25, 20 to 30,25 to 35, 30 to 40, 35 to 45, 40 to 50, 45 to 55, 50 to 60, 55 to 65, 60to 70, 65 to 75, 70 to 80, 75 to 85, 80 to 90, 85 to 95, 90 to 100, 95to 105, 100 to 110, 105 to 115, or 110 to 120 hours.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans at such a timing as underfasting, before meals, immediately after meals or after meals and at anω3 PUFA or EPA dose of 1800 mg or 2000 mg, the maximum plasma ω3 PUFAconcentration in steady state (Css max) is preferably at least 50 μg/mL,more preferably at least 100 μg/mL, still more preferably at least 150μg/mL, still more preferably at least 200 μg/mL, and most preferably atleast 300 μg/mL, as calculated with correction by subtraction of theplasma ω3 PUFA concentration before the administration of thecomposition. Alternatively, the Css max is preferably 10 to 1000 μg/mL,more preferably 20 to 500 μg/mL, still more preferably 50 to 400 μg/mL,still more preferably 100 to 300 μg/mL, and most preferably 150 to 200μg/mL. The minimum plasma ω3 PUFA concentration at steady state (Cssmin) is preferably at least 10 μg/mL, more preferably at least 20 μg/mL,still more preferably at least 30 μg/mL, still more preferably at least40 μg/mL, and most preferably at least 50 μg/mL. Alternatively, the Cssmin is preferably 10 to 500 μg/mL, more preferably 20 to 250 μg/mL,still more preferably 40 to 200 μg/mL, still more preferably 60 to 150μg/mL, and most preferably 75 to 95 μg/mL. The average plasma ω3 PUFAconcentration at steady state (Css ave) is preferably at least 30 μg/mL,more preferably at least 60 μg/mL, still more preferably at least 90μg/mL, still more preferably at least 120 μg/mL, and most preferably atleast 150 μg/mL. Alternatively, the Css ave is preferably 10 to 700μg/mL, more preferably 20 to 500 μg/mL, still more preferably 50 to 300μg/mL, still more preferably 100 to 200 μg/mL, and most preferably 130to 150 μg/mL.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans at such a timing as underfasting, before meals, immediately after meals or after meals and at anω3 PUFA or EPA dose of 3600 mg or 4000 mg, the maximum plasma ω3 PUFAconcentration in steady state (Css max) is preferably at least 100μg/mL, more preferably at least 200 μg/mL, still more preferably atleast 250 μg/mL, still more preferably at least 300 μg/mL, and mostpreferably at least 350 μg/mL, as calculated with correction bysubtraction of the plasma ω3 PUFA concentration before theadministration of the composition. Alternatively, the Css max ispreferably 10 to 1000 μg/mL, more preferably 100 to 800 μg/mL, stillmore preferably 200 to 600 μg/mL, still more preferably 250 to 500μg/mL, and most preferably 350 to 400 μg/mL. The minimum plasma ω3 PUFAconcentration at steady state (Css min) is preferably at least 50 μg/mL,more preferably at least 100 μg/mL, still more preferably at least 150μg/mL, still more preferably at least 170 μg/mL, and most preferably atleast 200 μg/mL. Alternatively, the Css min is preferably 10 to 500μg/mL, more preferably 20 to 250 μg/mL, still more preferably 40 to 200μg/mL, still more preferably 60 to 150 μg/mL, and most preferably 75 to95 μg/mL. The average plasma ω3 PUFA concentration at steady state (Cssave) is preferably at least 30 μg/mL, more preferably at least 60 μg/mL,still more preferably at least 90 μg/mL, still more preferably at least120 μg/mL, and most preferably at least 5150 μg/mL. Alternatively, theCss ave is preferably 10 to 700 μg/mL, more preferably 20 to 500 μg/mL,still more preferably 50 to 300 μg/mL, still more preferably 100 to 200μg/mL, and most preferably 130 to 150 μg/mL.

In a pharmacokinetic study conducted by orally administering theself-emulsifying composition to humans at such a timing as underfasting, before meals, immediately after meals or after meals and at anω3 PUFA or EPA dose per individual of 500 mg, 1000 mg, 1800 mg, 2000 mg,3600 mg, 4000 mg, 6000 mg or 8000 mg, the maximum plasma ω3 PUFAconcentration in steady state (Css max), the minimum plasma ω3 PUFAconcentration in steady state (Css min) and the average plasma ω3 PUFAconcentration in steady state (Css ave) as calculated with correction bysubtraction of the plasma ω3 PUFA concentration before theadministration of the composition are not particularly limited, whileeach of them may be specified to be: 10 to 110, 20 to 120, 30 to 130, 40to 140, 50 to 150, 60 to 160, 70 to 170, 80 to 180, 90 to 190, 100 to200, 110 to 210, 120 to 220, 130 to 230, 140 to 240, 150 to 250, 160 to260, 170 to 270, 180 to 280, 190 to 290, 200 to 300, 210 to 310, 220 to320, 230 to 330, 240 to 340, 250 to 350, 260 to 360, 270 to 370, 280 to380, 290 to 390, 300 to 400, 310 to 410, 320 to 420, 330 to 430, 340 to440, 350 to 450, 360 to 460, 370 to 470, 380 to 480, 390 to 490, 400 to500, 410 to 510, 420 to 520, 430 to 530, 440 to 540, 450 to 550, 460 to560, 470 to 570, 480 to 580, 490 to 590, 500 to 600, 510 to 610, 520 to620, 530 to 630, 540 to 640, 550 to 650, 560 to 660, 570 to 670, 580 to680, 590 to 690, 600 to 700, 610 to 710, 620 to 720, 630 to 730, 640 to740, 650 to 750, 660 to 760, 670 to 770, 680 to 780, 690 to 790, 700 to800, 810 to 910, 820 to 920, 830 to 930, 840 to 940, 850 to 950, 860 to960, 870 to 970, 880 to 980, 890 to 990, 900 to 1000, 10 to 30, 20 to40, 30 to 50, 40 to 60, 50 to 70, 60 to 80, 70 to 90, 80 to 100, 90 to110, 100 to 120, 110 to 130, 120 to 140, 130 to 150, 140 to 160, 150 to170, 160 to 180, 170 to 190, 180 to 200, 190 to 210, 200 to 220, 210 to230, 220 to 240, 230 to 250, 240 to 260, 250 to 270, 260 to 280, 270 to290, 280 to 300, 290 to 310, 300 to 320, 310 to 330, 320 to 340, 330 to350, 340 to 360, 350 to 370, 360 to 380, 370 to 390, 380 to 400, 390 to410, 400 to 420, 410 to 430, 420 to 440, 430 to 450, 440 to 460, 450 to470, 460 to 480, 470 to 490, 480 to 500, 490 to 510, 500 to 520, 510 to530, 520 to 540, 530 to 550, 540 to 560, 550 to 570, 560 to 580, 570 to590, 580 to 600, 590 to 610, 600 to 620, 610 to 630, 620 to 640, 630 to650, 640 to 660, 650 to 670, 660 to 680, 670 to 690, 680 to 700, 690 to710, 700 to 720, 710 to 730, 720 to 740, 730 to 750, 740 to 760, 750 to770, 760 to 780, 770 to 790, 780 to 800, 790 to 810, 800 to 820, 810 to830, 820 to 840, 830 to 850, 840 to 860, 850 to 870, 860 to 880, 870 to890, 880 to 900, 890 to 910, 900 to 920, 910 to 930, 920 to 940, 930 to950, 940 to 960, 950 to 970, 960 to 980, 970 to 990, 980 to 1000, 990 to1010, 1000 to 1020, 1010 to 1030, 1020 to 1040, 1030 to 1050, 1040 to1060, 1050 to 1070, 1060 to 1080, 1070 to 1090, 1080 to 1100, 1090 to1110, 1100 to 1120, 1110 to 1130, 1120 to 1140, 1130 to 1150, 1140 to1160, 1150 to 1170, 1160 to 1180, 1170 to 1190, or 1180 to 1200.

The present invention may be defined by a combination of two or moreselected from among the maximum plasma ω3 PUFA concentration, the plasmaω3 PUFA concentration 24 hours after the administration, the area underthe plasma ω3 PUFA concentration vs time curve from zero to 72 hoursafter the administration, the time until the maximum plasma ω3 PUFAconcentration is attained, and the plasma ω3 PUFA elimination half-life.

By administration, the self-emulsifying composition of the presentinvention is preferably capable of improving (reducing) at least oneparameter selected from TG, T-cho, LDL-C, non-HDL-C, VLDL-C, VLDL-TG,oxidized LDL, small dense LDL, remnant-like lipoprotein cholesterol,ApoB, ApoCIII, lipoprotein (a), Lp-PLA2, CETP activity, hs-CRP, plasmaphospholipid, free fatty acid, fasting blood glucose, HbA1c, HOMA-IR,intercellular adhesion molecule-1, IL-6, PAI-1, creatinine, AST, ALT,uric acid, 8-isoprostane, TXA2 and LTB2 and the metabolites thereof(HETE), and the like. The self-emulsifying composition of the presentinvention is also preferably capable of improving (increasing) at leastone parameter selected from HDL-C, apoA-I, apoA-I/ApoB ratio, EPA in theplasma or serum, EPA in the erythrocyte membrane or platelet membrane,and the like. The self-emulsifying composition of the present inventionis also preferably capable of reducing the number of LDL particles,increasing LDL particle size, and improving at least one parameterselected from ApoE genotype abnormality, hemoglobin abnormality,hematocrit abnormality, thrombocyte abnormality, and the like.

Particularly preferred is improvement (reduction) of at least oneparameter selected from small dense LDL, 8-isoprostane, and TXA2 andLTB2 and metabolites thereof (HETE).

Preferably, the amount of ω3 PUFA absorbed upon the administration ofthe self-emulsifying composition of the present invention is notsaturated by the high dose administration, and the maximum plasma ω3PUFA concentration, the plasma ω3PUFA concentration 24 hours after theadministration, or the area under the plasma ω3 PUFA concentration vstime curve preferably increases in dose dependent manner. When thecomposition is administered before, immediately after or after meals ata doubled EPA dose per individual within the range of 500 to 10000 mg(for example, 3600 mg for a dose of 1800 mg, 4000 mg for a dose of 2000mg, 8000 mg for a dose of 4000 mg, or the like), the value of themaximum plasma ω3 PUFA concentration, the plasma ω3 PUFA concentration24 hours after the administration, or the area under the plasma ω3 PUFAconcentration vs time curve becomes 1.2 times, preferably 1.5 times,more preferably 1.8 times, and most preferably 2.0 times higher.

When the ω3 PUFA is administered at a high dose, (for example, at adaily individual dose of 4000 mg) in order to realize the hightherapeutic effects, the excessive amount that could not be absorbed byhuman remains in the intestinal tract and this invites side effects oflower gastrointestinal tract or the like. In contrast, in the case ofthe self-emulsifying composition of the present invention, excellentabsorption is realized even in the case of the high dose administrationas described above, and the ω3 PUFA remaining in the intestinal tractwill be reduced or eliminated. The side effects are thereby reduced.

Examples of the side effects which can be reduced or eliminated includeside effects of lower gastrointestinal tract, nausea, abdominaldiscomfort, diarrhea, abdominal pain, heartburn, vomiting, anorexia,constipation, stomatiti, thirst, bloating, flatulence, etc.

When the self-emulsifying composition of the present invention isadministered at the timing other than during, after or immediately aftermeals, that is to say, at such a timing as under fasting (at least 8hours, and preferably at least 10 hours after the last meal), beforemeals, immediately before meals, between meals or at bedtime, or to apatient suffering from reduced absorption ability of the intestinaltract (elderly, patient with an intestinal disease, patient after theintestinal surgery, terminal cancer patient, patient taking a lipaseinhibitor), the results of the administration are preferably the same asother occasions.

For example, when the self-emulsifying composition is administered at atiming other than immediately after meals (for example, before meals)and at an EPA dose per individual of 1500 to 4200 mg (for example, 1800mg, 2000 mg, 3000 mg, 3600 mg or 4000 mg), the maximum plasma ω3 PUFAconcentration, the plasma ω3 PUFA concentration 24 hours after theadministration or the area under the plasma ω3 PUFA concentration vstime curve as calculated with correction by subtraction of the plasma ω3PUFA concentration before the administration of the composition ispreferably 50 to 150%, more preferably 60 to 140%, still more preferably70 to 130%, even more preferably 80 to 120%, and most preferably 90 to110% of the maximum plasma ω3 PUFA concentration, the plasma ω3 PUFAconcentration 24 hours after the administration or the area under theplasma ω3 PUFA concentration vs time curve in the case of theadministration immediately after meals.

The self-emulsifying composition of the present invention may alsocontain additives such as an emulsification aid, stabilizer, antiseptic,surfactant, and antioxidant. Exemplary emulsification aids include fattyacids containing 12 to 22 carbon atoms such as stearic acid, oleic acid,linoleic acid, palmitic acid, linolenic acid, and myristic acid andtheir salts. Exemplary stabilizers include phosphatidic acid, ascorbicacid, glycerin, and cetanols, and exemplary antiseptics include ethylparaoxybenzoate and propyl paraoxybenzoate. Exemplary surfactantsinclude sucrose fatty acid esters, sorbitan fatty acid esters, glycerinfatty acid esters, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters,polyoxyethylene alkyl phenyl ethers, and polyoxyethylenepolyoxypropylene alkyl ethers. Exemplary antioxidants includeoil-soluble antioxidants such as butylated hydroxy toluene, butylatedhydroxy anisole, propyl gallate, propyl gallate, pharmaceuticallyacceptable quinone, astaxanthin, and α-tocopherol.

In addition, an adequate carrier or vehicle, a colorant, a flavor, andoptionally, a vegetable oil and an additive such as non-toxic organicsolvent or non-toxic solubilizing agent, emulsifier, suspending agent(for example, Tween 80 and gum arabic solution), isotonic agent, pHadjusting agent, stabilizer, corrective, flavoring agent, preservative,antioxidant, or absorption promoter commonly used in the art may beadequately combined with the inventive composition to prepare anappropriate pharmaceutical preparation.

More specifically, since the ω3 PUFA is highly unsaturated, effectiveamount of an oil-soluble antioxidant, for example, at least one memberselected from butylated hydroxytoluene, butylated hydroxyanisole, propylgallate, propyl gallate, pharmaceutically acceptable quinone,astaxanthin, and α-tocopherol is preferably incorporated in thecomposition.

Since the self-emulsifying composition of the present invention is alsoused for pharmaceutical application, it preferably has good appearance,self-emulsifying property, composition dispersibility, emulsionstability, and storage stability. The appearance of the self-emulsifyingcomposition is such that the composition is not separated, clouded,solidified, or precipitated, but transparent. The composition havingpoor appearance may be pharmaceutically unsuitable, and such compositionmay be insufficient in required performance such as self-emulsifyingproperty.

With regard to the storage temperature, the self-emulsifying compositionand the preparation prepared by encapsulating such composition ispreferably transparent at both low temperature and high temperature inview of its use in cold district or hot environment.

In the case of the self-emulsifying composition having goodself-emulsifying property, good dispersibility of the composition, andhigh emulsion stability, the composition rapidly disperses upon contactwith water to form a microemulsion having adequate emulsion dropletdiameter. Absorbability of an oil such as EPA-E is related to the sizeof the emulsion droplet diameter, and degree of the absorbability uponadministration to the animal can be estimated by measuring the emulsiondroplet diameter.

In the present invention, the “mean droplet diameter” is the value ofvolume mean diameter among droplets of the emulsified compositionmeasured by using a particle size analyzer (for example, Nanotoracmanufactured by Nikkiso Co., Ltd.) with water being used for thedispersion medium according to standard measurement method (for example,set zero time of 30 seconds, measurement time of 30 seconds, average ofthree measurements). The mean droplet diameter when the self-emulsifyingcomposition of the present invention is dispersed in water or the likeis not particularly limited as long as it is up to 2 μm, and the producthas good emulsion dispersibility, good emulsion stability, or goodabsorbability, and the mean droplet diameter is typically up to 1.5 μm,more preferably up to 1.0 μm, still more preferably up to 0.5 μm, andmost preferably up to 0.3 μm.

The self-emulsifying composition of the present invention may be used bycombining with a second effective component. The second effectivecomponent may be any component adequately selected depending on theintended type and severity of the disease as long as it does notadversely affect the merits of the ω3 PUFAs. Exemplary such secondeffective components include therapeutic agents for hyperlipidemia,antihypertensives, antidiabetics, antioxidants, blood flow improvingagents, bile acid derivatives, therapeutic agents for NAFLD and NASH, aswell as progression suppressants and therapeutic agents for cognitiveimpairment.

Examples of a favorable second effective component include suchtherapeutic agents for hyperlipidemia as polyene phosphatidyl choline,unsaponifiable matter in soybean oil (soysterol), gamma orizanol,riboflavin butyrate, dextran sulfate sodium sulfur 18, pantethine, andelastase. Also included are statins such as pravastatin, simbastatin,atorvastatin, fluvastatin, pitavastatin, rosuvastatin and cerivastatin;fibrates such as simfibrate, clofibrate, clinofibrate, bezafibrate andfenofibrate; lipolytic enzyme inhibitors such as orlistat andcetilistat; resins such as cholestyramine and cholestyramide; andezetimibe.

Exemplary antihypertensives include: angiotensin II receptor antagonistssuch as irbesartan, olmesartan medoxomil, candesartan cilexetil,telmisartan, valsartan, and losartan potassium; angiotensin convertingenzyme inhibitors such as alacepril, imidapril hydrochloride, enalaprilmaleate, captopril, quinapril hydrochloride, cilazapril hydrate,temocapril hydrochloride, delapril hydrochloride, trandolapril,benazepril hydrochloride, perindopril, and lisinopril hydrate; calciumantagonists such as azelnidipine, amlodipine besylate, aranidipine,efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride,nifedipine, nimodipine, nitrendipine, nilvadipine, barnidipinehydrochloride, felodipine, benidipine, and manidipin; α-receptorblockers such as tolazoline and phentolamine; β-receptor blockers suchas atenolol, metoprolol, acebutolol, propranolol, pindolol, carvedilol,and labetalol hydrochloride; α-receptor stimulants such as clonidine andmethyldopa; and diuretics such as eplerenone, hydrochlorothiazide andfurosemide.

Exemplary antidiabetics include: α-glucosidase inhibitors such asacarbose, voglibose and miglitol; sulfonylurea hypoglycemic agents suchas gliclazide, glibenclamide, glimepiride and tolbutamide; short-actinginsulin secretagogues such as nateglinide and mitiglinide; biguanidehypoglycemic agents such as metformin hydrochloride and buforminhydrochloride; dipeptidyl phosphatase-4 inhibitors such as sitagliptin,vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin andsaxagliptin; thiazolidines such as pioglitazone hydrochloride androsiglitazone maleate; glucagon-like peptide 1 derivatives such asexenatide and liraglutide; and sodium-glucose cotransporter 2 inhibitorssuch as ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin,canagliflozin and empagliflozin.

Exemplary antioxidants include such vitamins as ascorbic acid (vitaminC), tocopherol (vitamin E) and tocopherol nicotinate ester,N-acetylcysteine, and probucol.

Exemplary blood flow improving agents include cilostazol, ticlopidinehydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelatehydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride,batroxobin, dihydroergotoxine mesylate, tolazoline hydrochloride,hepronicate, and shimotsuto extract.

Exemplary bile acid derivatives include ursodeoxycholic acid,chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bileextract, bear bile, oriental bezoar, and dehydrocholic acid. Favorableexamples are biotin (vitamin B7), cyanocobalamin (vitamin B12),pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine(vitamin B1), vitamin A, vitamin D, vitamin K, tyrosine, pyridoxine(vitamin B6), branched amino acids such as leucine, isoleucine andvaline, calcium, iron, zinc, copper, magnesium, and the like. Alsofavorable are such ingredients of foods for specified health use andfoods with nutrient function claims as soybean proteins, chitosan, lowmolecular-weight sodium alginate, dietary fiber derived from psylliumseed husks, soybean peptides bound to phospholipids, plant sterolesters, plant stanol esters, diacylglycerol, globin proteolysisproducts, and tea catechin.

Exemplary therapeutic agents for NAFLD and NASH include the statins suchas pravastatin, simbastatin, atorvastatin, fluvastatin, pitavastatin,rosuvastatin and cerivastatin; the angiotensin II receptor antagonistssuch as irbesartan, olmesartan medoxomil, candesartan lexetil,telmisartan, valsartan, and losartan potassium; the biguanidehypoglycemic agents such as metformin hydrochloride and buforminhydrochloride; and the thiazolidines such as pioglizone hydrochlorideand rosiglitazone maleate as mentioned above, as well as aspirin andfarnesoid X receptor (hereafter abbreviated as FXR) ligands such asursodeoxycholic acid, chenodeoxycholic acid and obeticholic acid.

Exemplary progression suppressants and therapeutic agents for cognitiveimpairment include acetylcholineesterase inhibitors such as donepezilhydrochloride and galantamine hydrobromide; NMDA receptor inhibitorssuch as memantine hydrochloride; antiplatelets such as aspirin,clopidogrel sulfate, cilostazol, and ticlopidine hydrochloride; andfactor Xa inhibitors such as rivaroxaban and apixaban. In addition, thetherapeutic agents for hyperlipidemia, antihypertensives, antidiabetics,antioxidants and blood flow improving agents as mentioned above are alsousable as progression suppressants and therapeutic agents for cognitiveimpairment.

To realize pharmacological actions of the ω3 PUFA, the self-emulsifyingcomposition of the present invention preferably has at least one meritselected from good appearance, good self-emulsifying property, highcomposition dispersibility, high emulsion stability, high storagestability (including the stability at low and high temperatures), highabsorbability, in particular high absorbability and high absorptionspeed under fasting conditions, absorbability independent of diet,convenience to patients taking the composition, reduction in sideeffects, and a preparation of easy compliance.

The self-emulsifying composition of the present invention is welladapted for use as a therapeutic agent for treating various diseases ofanimals, mammals in particular, that is to say, is usable as, forinstance, therapeutic agent for dyslipidemia (hypercholesterolemia, LDLhypercholesterolemia, non-HDL hypercholesterolemia, VLDLhypercholesterolemia, HDL hypocholesterolemia, hypertriglyceridemia, apoB hyperlipoproteinemia, apo A-I hypolipoproteinemia, increased LDLparticle number-emia, small LDL particle size-emia, hyper-oxidizedLDL-emia, hyper-small dense LDL-emia, hyper-RLP-C-emia, hypo-apoA-I/ApoBratio-emia, hyper-ApoCIII-emia, dys-ApoE genotype-emia,hyper-lipoprotein (a)-emia, hyper-Lp-PLA2-emia, hyper-CETPactivity-emia, hyper-hs-CRP-emia, hypo-EPA-emia (the state wherein EPAvalue in plasma, serum, erythrocyte membrane, platelet membrane is low),hyper-free fatty acidemia), hyper-fasting glucose-emia,hyper-HbA1c-emia, hyper-HOMA-IR-emia, hyper-intercellular adhesionmolecule-1-emia, hyper-IL-6-emia, hyper-PAI-1-emia, hypercreatininemia,hyper-AST-emia, hyper-ALT-emia, hyper-uric acidemia,hyper-8-isoprostane-emia, hyper-TXA2-emia, hyper-LTB2-emia, and soforth), therapeutic agent for postprandial hypertriglyceridemia,anti-arteriosclerotic, platelet aggregation suppressant, therapeuticagent for peripheral circulatory insufficiency, prophylactic agent forcardiovascular events, therapeutic agent for inflammatory disease(NAFLD, NASH, and so forth), progression suppressant and therapeuticagent for cognitive impairment (dementia of the Alzheimer's type,cerebrovascular dementia, mixed type of dementia, and so forth),anticancer agent, and therapeutic agent for central disease (depression,depressive condition, obsessive-compulsive disorder, social anxietydisorder, panic disorder, and so forth). In the treatment of thediseases as above, the inventive self-emulsifying composition is notparticularly limited in frequency of administration per day, and ispreferably administered one time a day at the entire daily dose or twoor three times a day at divided doses, with one or two timeadministration per day being more preferable and one time administrationper day most preferable.

The self-emulsifying composition of the present invention isparticularly effective for the amelioration or treatment of dyslipidemiaand postprandial hypertriglyceridemia, and the prevention of theirrecurrence or progression to metabolic syndrome, cardiocerebrovascularevents, and ulcer or gangrene at a limb distal end. Exemplary mammalsinclude human, domestic animals such as cattle, horse, and pig, andcompanion animals such as dog, cat, rabbit, rat, and mouse, and thepreferred is human. More specifically, the self-emulsifying compositionof the present invention is anticipated to show ameliorating ortherapeutic effects for dyslipidemia and postprandialhypertriglyceridemia in patients with dyslipidemia suffering fromincrease in the blood lipid, exhibiting insulin resistance or sufferingfrom increase in the blood pressure, such as metabolic syndromepatients.

EXAMPLES

Next, the present invention is described in further detail by referringto the following Examples and Comparative Examples which by no meanslimit the scope of the invention.

Example 1

0.09 g of water, 0.53 g of polyoxyethylene (20) sorbitan oleate, 0.39 gof soybean lecithin, and 4.0 g of EPA-E were weighed, sealed, and mixedwhile heating to about 70° C. to thereby prepare the self-emulsifyingcomposition. The self-emulsifying composition was sealed after purgingwith nitrogen, and stored at room temperature until the evaluation wasconducted. Formulation of the self-emulsifying composition is shown inTable 1.

Examples 2 to 11 and Comparative Examples 1 and 2

The self-emulsifying compositions of Examples 2 to 8 and thecompositions of Comparative Examples 1 and 2 were prepared and stored byrepeating the method of Example 1 so that the compositional ratios wereas shown in Table 1. Formulations of the self-emulsifying compositionsand the compositions are shown in Table 1.

Comparative Examples 3 and 4

The compositions of Comparative Examples 3 and 4 were prepared andstored by repeating the method of Example 1 so that the compositionalratios were as shown in Table 1. Formulations of the compositions areshown in Table 1.

The self-emulsifying compositions and the compositions of ComparativeExamples as produced by the method as described above were eachencapsulated in the capsule containing gelatin as its main component.

Test Example 1 <Evaluation of Appearance>

The self-emulsifying compositions and the compositions of ComparativeExamples as produced by the above production method were allowed tostand, and after about 1 hour, their appearance was evaluated. When thecomposition was homogeneous due to the good compatibility, thecomposition was evaluated as “transparent.” The composition wasevaluated as “separated” when the separation was observed, and as“cloudy” when opacity was observed.

The results are shown in Table 1.

Test Example 2 <Evaluation of Self-Emulsifying Property>

The self-emulsifying compositions and the compositions of ComparativeExamples as produced by the above production method were evaluated forself-emulsifying property by adding 10 μL of each composition dropwiseto 5 mL of purified water or first fluid for dissolution test ofJapanese Pharmacopeia at 37° C. in the test tube. The composition whichspontaneously emulsified just by the dropwise addition was evaluated as“good,” and the case which did not become an emulsion just by thedropwise addition was evaluated as “poor.” The composition was thenlightly stirred under consistent condition, and examined for otherproperties. With regard to the dispersibility of the composition, thecomposition was evaluated as “good” when dispersed and as “poor” whenthe composition was partly left undispersed as a mass. With regard tothe emulsion stability, the composition was evaluated as “good” when nooil separation was observed, and as “poor” when oil separation wasobserved. It is to be noted that the compositions which were notevaluated as “transparent” in the appearance evaluation were notevaluated in such properties since inhomogeneous compositions wereconceived to be inadequate for property evaluation.

The results are shown in Table 1.

Test Example 3 <Evaluation of Emulsion Droplet Diameter>

Using about 1.5 mL of the emulsified composition as obtained in TestExample 2, the mean droplet diameter (volume mean diameter) was measuredby a particle size analyzer (Nanotorac, manufactured by Nikkiso Co.,Ltd.) using water as a dispersion medium.

Test Example 4 <Evaluation of the Appearance after Storage Under SevereConditions>

The compositions which were evaluated as “transparent” or “cloudy” inTest Example 1 were allowed to stand and stored overnight (for about 12hours) at 5° C. or 40° C. before their appearance was evaluated. Whenthe composition was homogeneous due to its good compatibility, thecomposition was evaluated as “transparent.” The composition wasevaluated as “separated” when the separation was observed, and as“cloudy” when opacity was observed.

The results are shown in Table 1.

Test Example 5 <Pharmacokinetics in Beagles>

The produced compositions or capsules (Examples 1, 3 and 5) were eachorally administered to 6 male beagles (at the age of 2 to 6 years withthe body weight of 8 to 13 kg, 3 Marshall beagles and 3 Nosan beagles)under fasting conditions, and blood EPA concentration was evaluated. Thetest animals had been fasted since 18 hours or more before theadministration, and each animal was administered with the composition inan amount corresponding to 600 mg of the EPA-E. Blood was collectedbefore the administration, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hoursafter the administration, and plasma was separated to measure plasma EPAconcentration by LC/MS/MS (method in which a sample is isolated byliquid chromatography, then subjected to mass spectrometry to conductseparation and measurement thereon). The control group was administeredwith the EPA-E stock solution encapsulated in a capsule.

Table 1 shows the maximum plasma ω3 PUFA concentration (Cmax), the areaunder the plasma ω3 PUFA concentration vs time curve from zero to twohours (AUC₀₋₂) and the area under the plasma ω3 PUFA concentration vstime curve from zero to 24 hours (AUC₀₋₂₄) as calculated from the testresults. In the calculation of each parameter, correction was made bysubtracting the blood EPA concentration before the administration fromthe measured blood concentration.

Test Example 6 <Pharmacokinetics in Crab-Eating Macaques>

The produced compositions or capsules are orally administered to 6crab-eating macaques (at the age of 2 to 5 years with the body weight of2.70 to 4.65 kg; Hamuri) under fasting conditions, and blood EPAconcentration is evaluated. The test animals are fasted for 12 hours ormore before the administration, and each animal is administered with theself-emulsifying composition in an amount corresponding to 45 mg/kg bodyweight of the EPA-E. The control group is administered with the EPA-Estock solution encapsulated in a capsule. Blood is collected before theadministration, and 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours after theadministration, and plasma is separated to measure EPA in plasma byLC/MS/MS. From the test results, the maximum plasma ω3 PUFAconcentration (Cmax), the area under the plasma ω3 PUFA concentration vstime curve from zero to 12 hours (AUC₀₋₁₂), and the area under theplasma ω3 PUFA concentration vs time curve from zero to 72 hours(AUC₀₋₇₂) are calculated. In the calculation of each parameter,correction is made by subtracting the blood EPA concentration before theadministration from the measured blood concentration.

In the animals having the compositions administered thereto, values ofblood concentration parameters, such as the Cmax and the AUC₀₋₁₂, areincreased as compared with the control group. More specifically, it isconfirmed that, when the self-emulsifying composition of the presentinvention is administered, amount of the EPA absorbed is increased, andalso, EPA absorption is rapid after the oral administration.

Test Example 6-2 <Pharmacokinetics in Humans (Single Dose AdministrationTest, Administration of 1800 mg)>

The capsule having the self-emulsifying composition of the presentinvention containing 80% by weight of EPA-E as its content was orallyadministered to human (12 cases, healthy adult males of 20 to 40 yearsold with a body weight of 55.0 to 77.0 kg and a BMI of 18.5 or more butless than 25.0) under fasting conditions to evaluate the change of bloodEPA concentration. The self-emulsifying composition in an amountcorresponding to 1800 mg of EPA-E was orally administered in single doseto each human who had been fasted since 10 hours or more before theadministration by using 200 mL of water in the morning under fasting.The blood was collected 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15,18, 24, 48 and 72 hours after the administration. Immediately after thecollection, the blood was cooled on ice, and centrifuged at 2000×g at 4°C. for 10 minutes to separately collect the plasma. After having storedthe resulting plasma at a temperature not higher than −20° C. in frozenstate, concentration of the EPA in the plasma was measured by LC/MS/MS(method in which a sample is isolated by liquid chromatography, thensubjected to mass spectrometry to conduct separation and measurementthereon).

The capsule having the self-emulsifying composition of the presentinvention containing 80% by weight of EPA-E as its content was alsoorally administered to human immediately after meals, and themeasurement was conducted by repeating the procedure as described above.

For the control group, the EPA-E stock solution (high purity EPA-E (atleast 96.5% by weight) containing no emulsifier or the like and usedwith the same EPA-E amount as that of the self-emulsifying compositionof the present invention; the same applying hereafter) filled in thecapsule was orally administered to human (12 cases, healthy adult malesof 20 to 40 years old with a body weight of 55.0 to 77.0 kg and a BMI of18.5 or more but less than 25.0) under fasting conditions (fasting sinceat least 10 hours before the administration), and the measurement wasconducted by repeating the procedure as described above.

Table 2 shows the maximum plasma concentration (Cmax), the plasma ω3PUFA concentration 24 hours after the administration (C₂₄), the areaunder the plasma ω3 PUFA concentration vs time curve from zero to 72hours (AUC₀₋₇₂), the time until the maximum plasma ω3 PUFA concentrationis attained (Tmax), and the plasma ω3 PUFA elimination half-life(t_(1/2)) as calculated from the test results. In the calculation ofeach parameter, correction was made by subtracting the blood EPAconcentration before the administration from the measured bloodconcentration.

Test Example 6-3 <Pharmacokinetics in Humans (Single Dose AdministrationTest, Administration of 3600 mg)>

The test procedure of the Test Example 6-2 was repeated except that thedose per individual was 3600 mg. This test was conducted on 6 humans.Table 3 shows the maximum plasma ω3 PUFA concentration (Cmax), theplasma ω3 PUFA concentration 24 hours after the administration (C₂₄),the area under the plasma ω3 PUFA concentration vs time curve from zeroto 72 hours (AUC₀₋₇₂), the time until the maximum plasma ω3 PUFAconcentration is attained (Tmax), and the plasma ω3 PUFA eliminationhalf-life (t_(1/2)) as calculated from the test results. In thecalculation of each parameter, correction was made by subtracting theblood EPA concentration before the administration from the measuredblood concentration.

Test Example 6-4 <Pharmacokinetics in Humans (Continuous AdministrationTest)>

The capsule having the self-emulsifying composition of the presentinvention containing 80% by weight of EPA-E as its content is orallyadministered to human (healthy adult males of 20 to 40 years old with abody weight of 55.0 to 77.0 kg and a BMI of 18.5 or more but less than25.0) once a day immediately after morning meals for 11 days to evaluatethe change of blood EPA concentration. The self-emulsifying compositionin an amount corresponding to 500, 1000, 2000, 40000, 6000 or 8000 g ofEPA-E is orally administered to each human by using 200 mL of water.Three meals are to be taken daily. The blood is collected 1, 2, 3, 4, 5,6, 8, 10, 12, 18 and 24 hours after the administration at days 1 and 11of administration (“24 hours after the administration” refers to “justbefore the administration on the next day”), and 24 hours after theadministration at days 2 to 10. Immediately after the collection, theblood is cooled on ice, and centrifuged at 2000×g at 4° C. for 10minutes to separately collect the plasma. After storing the resultingplasma at a temperature not higher than −20° C. in frozen state,concentration of the EPA in the plasma is measured by LC/MS/MS.

For the control group, a capsule having the EPA-E stock solution filledin the capsule is orally administered to human (healthy adult males of20 to 40 years old with a body weight of 55.0 to 77.0 kg and a BMI of18.5 or more but less than 25.0) in an amount corresponding to 1800 mgof the EPA-E once a day immediately after morning meals for 11 days, andchange in the blood EPA concentration is evaluated by repeating theprocedure as described above.

The capsule having the self-emulsifying composition of the presentinvention containing 80% by weight of EPA-E as its content is alsoorally administered to human under fasting conditions, and themeasurement is conducted by repeating the procedure as described above.

From the test results, the maximum plasma ω3 PUFA concentration (Cmax),the area under the plasma ω3 PUFA concentration vs time curve from zeroto 24 hours (AUC₀₋₂₄), the time until the maximum plasma ω3 PUFAconcentration is attained (Tmax) and the plasma ω3 PUFA eliminationhalf-life (t_(1/2)) at day 1 of administration and the plasma ω3 PUFAconcentration 24 hours after the administration (C₂₄) at days 1 to 11are calculated. The maximum plasma ω3 PUFA concentration in steady state(Css max), the minimum plasma ω3 PUFA concentration in steady state (Cssmin) and the average plasma ω3 PUFA concentration in steady state (Cssave) are also calculated. In the calculation of each parameter,correction is made by subtracting the blood EPA concentration before theadministration from the measured blood concentration.

Test Example 7 <Appearance of the Capsule>

The soft capsules obtained in the Examples were visually inspected forthe color and shape of the capsule and the property of the capsulecontent after the completion of filling and drying.

The capsules with change in the “color”, distortion, depression, or thelike in the “shape”, and cloudiness, separation, or the like in the“property of the capsule content” were evaluated as “poor,” and thecapsules without such problems were evaluated as “normal.”

The test results are shown in Table 1. In the Table below, “-” meansthat the corresponding component was not added or that the correspondingitem was not measured.

TABLE 1 Component Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Filled in capsuleYes Yes Yes — Yes Yes Ethyl eicosa- 80.0 75.0 80.0 80.0 80.0 83.0pentaenoate Purified water 1.7 1.1 1.2 1.2 2.0 1.0 Polyoxyethylene 10.510.8 7.2 6.5 5.8 8.5 (20) sorbitan oleate Polyoxyethylene — — — — — —sorbitan trioleate Polyoxyl 35 castor — 10.8 7.2 7.9 5.8 4.5 oilPolyoxyethylene — — — — — — (60) hydrogenated castor oil Soybeanlecithin 7.8 2.4 4.4 4.4 6.4 3.0 Propylene glycol — — — — — — Total100.0 100.0 100.0 100.0 100.0 100.0 Test. Appearance TransparentTransparent Transparent Transparent Transparent Transparent Ex. 1 Test.Self- Good Good Good Good — Good Ex. 2 emulsifying property CompositionGood Good Good Good — Good dispersibility Emulsion Good Good Good Good —Good stability Test. Purified 0.44 0.34 0.27 — 0.35 0.25 Ex. 3 water atEmulsion 37° C. drop- (μm) let Japanese 0.36 0.29 0.22 — 0.57 0.29 diam.Pharmacopeia, 1st fluid, 37° C. (μm) Test. Stored at TransparentTransparent Transparent Transparent Transparent Transparent Ex. 4 5° C.Appearance Stored at Transparent Transparent Transparent TransparentTransparent Transparent 40° C. Test. Cmax 104.7 — 128.7 — 80.0 — Ex. 5AUC₀₋₂ 94.0 — 97.8 — 60.7 — AUC₀₋₂₄ 617.8 — 1036.3 — 566.6 — Test.Capsule Normal Normal Normal — Normal Normal Ex. 6 appearance Ex. Ex.Comp. Component Ex. 7 Ex. 8 Ex. 9 10 11 Ex. 1 Filled in capsule — — — —— — Ethyl eicosa- 80.0 80.0 80.0 80.0 83.0 80.0 pentaenoate Purifiedwater 1.2 1.2 4.0 2.0 2.0 — Polyoxyethylene 11.1 13.1 5.1 — 8.0 7.2 (20)sorbitan oleate Polyoxyethylene — — — 5.8 — — sorbitan trioleatePolyoxyl 35 castor 3.3 1.3 5.1 5.8 — 7.2 oil Polyoxyethylene — — — — 4.0— (60) hydrogenated castor oil Soybean lecithin 4.4 4.4 5.8 6.4 3.0 5.6Propylene glycol — — — — — — Total 100.0 100.0 100.0 100.0 100.0 100.0Test. Appearance Transparent Transparent Transparent TransparentTransparent Separated Ex. 1 Test. Self- Good Good Good Good Good Not Ex.2 emulsifying evaluated property Composition Good Good Good Good Gooddispersibility Emulsion Good Good Good Good Good stability Test.Purified — — 0.28 — — Ex. 3 water at Emulsion 37° C. drop- (μm) letJapanese — — 0.32 — — diam. Pharmacopeia, 1st fluid, 37° C. (μm) Test.Stored at Transparent Transparent Transparent Transparent TransparentEx. 4 5° C. Appearance Stored at Transparent Transparent TransparentTransparent Transparent 40° C. Test. Cmax — — — — — Ex. 5 AUC₀₋₂ — — — —— AUC₀₋₂₄ — — — — — Test. Capsule — — — — — Ex. 6 appearance Comp. Ex. 5EPA-E stock solution Comp. Comp. Comp. (Fasted Component Ex. 2 Ex. 3 Ex.4 control) Filled in capsule — — — Ethyl eicosa- 80.0 75.2 80.0pentaenoate Purified water 8.0 — 1.2 Polyoxyethylene 3.8 5.8 — (20)sorbitan oleate Polyoxyethylene — — — sorbitan trioleate Polyoxyl 35castor 3.8 5.8 14.4 oil Polyoxyethylene — — — (60) hydrogenated castoroil Soybean lecithin 4.4 6.5 4.4 Propylene glycol — 6.7 — Total 100.0100.0 100.0 Test. Appearance Separated Transparent Cloudy Ex. 1 Test.Self- Not Good Good Ex. 2 emulsifying evaluated property CompositionGood Good dispersibility Emulsion Good Good stability Test. Purified0.15 — Ex. 3 water at Emulsion 37° C. drop- (μm) let Japanese 0.18 —diam. Pharmacopeia, 1st fluid, 37° C. (μm) Test. Stored at TransparentCloudy Ex. 4 5° C. Appearance Stored at Separated Cloudy 40° C. Test.Cmax — — 18.4 Ex. 5 AUC₀₋₂ — — 11.3 AUC₀₋₂₄ — — 76.6 Test. Capsule — — —Ex. 6 appearance

TABLE 2 Control Capsule Capsule group, preparation of preparation ofEPA-E Test Example Test Example 6- Test Example 6- stock 6-2 2 (Dose,1800 mg) 2 (Dose, 1800 mg) solution Meal No Yes No Cmax (μg/mL) 65.1111.3 4.6 C 24 hr (μg/mL) 19.5 28.6 2.4 AUC 0-72 hr 1266.0 1932.1 113.1(μg · hr/mL) Tmax (hr) 5.2 3.3 10.8 t½ (hr) 31.2 42.6 71.7

TABLE 3 Control Capsule Capsule group, preparation of preparation ofEPA-E Test Example Test Example 6- Test Example 6- stock 6-3 2 (Dose,3600 mg) 2 (Dose, 3600 mg) solution Meal No Yes No Cmax (μg/mL) 174.2184.5 3.6 C 24 hr (μg/mL) 36.4 37.7 1.2 AUC 0-72 hr 2845.5 2615.9 113.7(μg · hr/mL) Tmax (hr) 5.2 4.3 21.8 t½ (hr) 58.7 42.4 22.8

Example 1 is the composition containing polyoxyethylene sorbitan fattyacid ester as the only emulsifier together with certain amounts oflecithin and water, and as shown in Table 1, this composition had goodappearance as well as excellent self-emulsifying property. This resultindicates that the merits of the present invention are realized by thecomposition containing lecithin wherein the polyoxyethylene sorbitanfatty acid ester is the only emulsifier.

Examples 2 to 10 are compositions containing polyoxyethylene castor oilas an additional emulsifier. These compositions also exhibited goodappearance as well as excellent self-emulsifying property as shown inTable 1.

Example 11 is a composition containing polyoxyethylene hydrogenatedcastor oil as an additional emulsifier. This composition also exhibitedgood appearance as well as excellent self-emulsifying property as shownin Table 1.

Comparative Example 1 is a composition not containing the water, andthis composition became separated. Comparative Example 2 is acomposition containing 8% by weight of water, and this composition alsobecame separated.

In the present invention, water was used instead of adding the ethanolor the polyhydric alcohol to thereby improve the compatibility of thecomposition. The composition became separated due to inadequatecompatibility when no water was used, while the composition stillseparated even with the use of water when the amount of water was toomuch in relation to the amount of the composition. In the meanwhile, theseparation did not occur in Examples 1 to 6 containing 1 to 4% by weightof water. These results indicate that presence of a certain amount(approximately 0.5 to 6% by weight) of water is important for the goodappearance.

Comparative Example 3 is a composition not containing water butcontaining polyhydric alcohol. As in the case of Example 1, thiscomposition had good appearance as well as good self-emulsifyingproperty.

However, the composition of Comparative Example 3 separated afterovernight storage at 40° C., and this demonstrates importance of addinga particular amount (approximately 0.5 to 6% by weight) of water to thecomposition in view of improving the appearance and the like.

Comparative Example 4 is a composition containing polyoxyethylene castoroil for the emulsifier and not containing the polyoxyethylene sorbitanfatty acid ester, and in the case of this composition, the compositionhad cloudy appearance.

This demonstrates the importance of the incorporation of thepolyoxyethylene sorbitan fatty acid ester as the emulsifier for the goodappearance.

Examples 1, 3, and 5 show the kinetics when the self-emulsifyingcomposition was added to fasted animals.

In the animals having these self-emulsifying compositions administeredthereto, Cmax and AUC₀₋₂ values which are the parameters of theabsorption speed were significantly higher than those in the controlgroup animals (under fasting) administered with the EPA-E stock solutionas a control. More specifically, it was confirmed that, when theself-emulsifying compositions of the Examples were administered, amountof the EPA absorbed until 24 hours after the oral administrationincreased, and also, EPA absorption was rapid especially after the oraladministration compared to the control group.

Test Example 6-2 shows parameters when the self-emulsifying compositionof the present invention containing 80% by weight of the EPA-E in anamount corresponding to 1800 mg of EPA-E and 1800 mg of EPA-E wererespectively administered to human. Under the fasting conditions, all ofthe parameters Cmax, C₂₄ and AUC₀₋₇₂ were about 10 times higher in thecase of the composition of the Example (Cmax was 14.2 times higher, C₂₄was 8.1 times higher, and AUC₀₋₇₂ was 11.2 times higher), and rapidabsorption of the EPA after the oral administration was confirmed. TestExample 6-3 shows the parameters when the inventive self-emulsifyingcomposition in an amount corresponding to 3600 mg of EPA-E and 3600 mgof EPA-E were respectively administered, and the parameters were severaltens times higher (Cmax was 48.4 times higher, C₂₄ was 30.3 timeshigher, and AUC₀₋₇₂ was 25.0 times higher), confirming similar rapidabsorption. It was also confirmed that the self-emulsifying compositionof the present invention was less likely to be affected by the meal, andthat it exhibits high EPA absorption irrespective of whether it is takenbefore or after meals.

Accordingly, the self-emulsifying composition of the present inventionwould be a candidate for the self-emulsifying preparation capable ofrapidly and markedly increasing the blood EPA concentration with rapidand effective pharmacological action even if taken under fastingconditions, that is to say, taken before meals, at bedtime or the like.

Self-Emulsifying Capsule Preparations of Examples 2-1 and 2-2 andCapsule Preparation of Comparative Example 2-3

The self-emulsifying compositions and the composition of ComparativeExample 2-3 were prepared and stored by repeating the procedure ofExample 1 so that the compositional ratios were as shown in Table 4. Theformulations of the self-emulsifying compositions are shown in Table 4.

375 mg of the self-emulsifying composition was filled in the capsule inExamples 2-1 and 2-2, and 441 mg of the self-emulsifying composition wasfilled in the capsule in Comparative Example 2-3 (300 mg of EPA-E inboth cases). In each case, the soft gelatin capsule having the contentfilled therein was produced by rotary method. Deformation of the capsulefilm was not noticed for the self-emulsifying capsule preparationsprepared by this method.

The compositional ratios of the encapsulated contents are shown in Table4.

Test Example 8 <Hardness of the Capsule>

The capsule preparations of Examples 2-1 and 2-2 and Comparative Example2-3 were measured in hardness. The preparations after storage at 40° C.and a relative humidity of 75% for 1, 2, and 4 weeks were also measuredin hardness.

The results at the initial stage and the results after the storage at40° C. for 1, 2, and 4 weeks are shown in Table 4. The preparation atthe initial stage refers to the preparation which has been stored atroom temperature after its production until the evaluation of thehardness. Since having been stored at 40° C. as sealed in aluminumpackages, the preparations were not affected by the moisture.

TABLE 4 Ex. Ex. Comp. Ex. 2-1 2-2 2-3 Component wt % wt % wt % Ethyleicosapentaenoate 80.0 80.0 68.0 Purified water 2.0 1.8 —Polyoxyethylene (20) 5.8 5.8 7.1 sorbitan oleate Polyoxyl 35 castor oil5.8 5.8 7.1 Soybean lecithin 6.4 6.4 9.5 Zymolytic lecithin — 0.2 —Tocopherol — — — Sodium erythorbate {circumflex over ( )} — — Propyleneglycol — — 8.3 Total 100.0 100.0 100.0 Test Ex. 7 Initial stage 28.924.7 15.7 Hardness 40° C., 1 week 25.5 22.3 9.1 (kgf) 40° C., 2 weeks24.5 20.5 8.9 40° C., 4 weeks 27.4 22.3 8.1

Examples 2-1 and 2-2 are preparations produced by encapsulating theself-emulsifying composition of the present invention. These capsuleshad a hardness of 20 kgf or higher. The hardness of the capsule isdetermined by measuring the hardness of the capsule preparationcontaining the composition of the present invention with a commonhardness tester.

On the other hand, the composition of Comparative Example 2-3 contains alarger amount (8.3% by weight) of propylene glycol (a polyhydricalcohol), and the hardness of the capsule preparation was alreadyinferior compared to Examples at the initial stage. When the hardnesswas evaluated after storing in sealed environment at 40° C. for 1 to 4weeks, substantially no change was noticed in Examples 2-1 and 2-2,while, in Comparative Example 2-3, the hardness declined to 57% of theinitial hardness in 1 week, and further declined with time.

Examples 3-1 to 3-252

The self-emulsifying compositions of Examples 3-1 to 3-252 are preparedand stored by the method of Example 1 so as to have the compositionalratios as shown in Tables 5 to 21. It is noted that the self-emulsifyingcomposition of some of these formulations were prepared and stored.Formulations of the self-emulsifying compositions and the compositionsare shown in Tables 5 to 21.

TABLE 5 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-1 3-2 3-3 3-4 3-5 3-6 3-7 3-8 3-9 3-10 3-11 3-12 3-13 3-143-15 Ethyl eicosapentaenoate 76 76 76 76 76 76 76 76 76 76 76 76 76 7676 Purified water 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.9 0.9 0.9 0.9 0.9 0.90.9 1.0 Polyoxyethylene (20) 12.2 11.8 11.3 10.7 10.0 9.2 8.3 12.3 11.811.3 10.7 10.0 9.2 8.4 12.3 sorbitan oleate Polyoxyl 35 castor oil 6.16.5 7.0 7.6 8.3 9.2 10.0 6.1 6.6 7.1 7.7 8.4 9.2 10.0 6.2 Soybeanlecithin 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.5Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 6 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-16 3-17 3-18 3-19 3-20 3-21 3-22 3-23 3-24 3-25 3-26 3-273-28 3-29 3-30 Ethyl eicosapentaenoate 76 76 76 76 76 76 76 76 76 76 7676 76 76 76 Purified water 1.0 1.0 1.0 1.0 1.0 1.0 1.2 1.2 1.2 1.2 1.21.2 1.2 1.5 1.5 Polyoxyethylene (20) 11.9 11.4 10.8 10.1 9.3 8.4 12.311.9 11.4 10.8 10.1 9.3 8.4 12.3 11.8 sorbitan oleate Polyoxyl 35 castoroil 6.6 7.1 7.7 8.4 9.3 10.1 6.2 6.6 7.1 7.7 8.4 9.3 10.1 6.1 6.6Soybean lecithin 4.5 4.5 4.5 4.5 4.5 4.5 4.3 4.3 4.3 4.3 4.3 4.3 4.3 4.14.1 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 7 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-31 3-32 3-33 3-34 3-35 3-36 3-37 3-38 3-39 3-40 3-41 3-423-43 3-44 3-45 Ethyl eicosapentaenoate 76 76 76 76 76 76 76 76 76 76 7676 77 77 77 Purified water 1.5 1.5 1.5 1.5 1.5 2.4 2.4 2.4 2.4 2.4 2.42.4 0.6 0.6 0.6 Polyoxyethylene (20) 11.3 10.7 10.0 9.2 8.4 11.0 10.610.2 9.6 9.0 8.3 7.5 11.5 11.1 10.6 sorbitan oleate Polyoxyl 35 castoroil 7.1 7.7 8.4 9.2 10.0 5.5 5.9 6.3 6.9 7.5 8.3 9.0 5.8 6.2 6.7 Soybeanlecithin 4.1 4.1 4.1 4.1 4.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1 5.1Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 8 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-46 3-47 3-48 3-49 3-50 3-51 3-52 3-53 3-54 3-55 3-56 3-573-58 3-59 3-60 Ethyl eicosapentaenoate 77 77 77 77 77 77 77 77 77 77 7777 77 77 77 Purified water 0.6 0.6 0.6 0.6 0.9 0.9 0.9 0.9 0.9 0.9 0.91.2 1.2 1.2 1.2 Polyoxyethylene (20) 10.1 9.4 8.7 7.9 12.0 11.6 11.110.5 9.8 9.0 8.2 11.7 11.3 10.8 10.2 sorbitan oleate Polyoxyl 35 castoroil 7.2 7.9 8.7 9.4 6.0 6.4 6.9 7.5 8.2 9.0 9.8 5.8 6.3 6.7 7.3 Soybeanlecithin 5.1 5.1 5.1 5.1 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.3 4.3 4.3 4.3Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 9 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-61 3-62 3-63 3-64 3-65 3-66 3-67 3-68 3-69 3-70 3-71 3-723-73 3-74 3-75 Ethyl eicosapentaenoate 77 77 77 77 77 77 77 77 77 77 7777 77 77 77 Purified water 1.2 1.2 1.2 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.81.8 1.8 1.8 1.8 Polyoxyethylene (20) 9.5 8.8 8.0 11.3 10.9 10.5 9.9 9.38.5 7.7 11.0 10.6 10.2 8.6 9.0 sorbitan oleate Polyoxyl 35 castor oil8.0 8.8 9.5 5.7 6.1 6.5 7.1 7.7 8.5 9.3 5.5 5.9 6.3 6.9 7.5 Soybeanlecithin 4.3 4.3 4.3 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.7 4.7 4.7 4.7 4.7Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 10 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-76 3-77 3-78 3-79 3-80 3-81 3-82 3-83 3-84 3-85 3-86 3-873-88 3-89 3-90 Ethyl eicosapentaenoate 77 77 77 77 77 77 77 77 77 78 7878 78 78 78 Purified water 1.8 1.8 2.4 2.4 2.4 2.4 2.4 2.4 2.4 0.8 0.80.8 0.8 0.8 0.8 Polyoxyethylene (20) 8.3 7.5 10.5 10.1 9.7 9.2 8.6 7.97.1 11.0 10.6 10.2 9.6 9.0 8.3 sorbitan oleate Polyoxyl 35 castor oil8.3 9.0 5.2 5.6 6.0 6.5 7.1 7.9 8.6 5.5 5.9 6.3 6.9 7.5 8.3 Soybeanlecithin 4.7 4.7 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.7 4.7 4.7 4.7 4.7 4.7Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 11 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-91 3-92 3-93 3-94 3-95 3-96 3-97 3-98 3-99 3-100 3-101 3-1023-103 3-104 3-105 Ethyl eicosapentaenoate 78 78 78 78 78 78 78 78 78 7878 78 78 78 78 Purified water 0.8 0.9 0.9 0.9 0.9 0.9 0.9 0.9 1.0 1.01.0 1.0 1.0 1.0 1.0 Polyoxyethylene (20) 7.5 11.1 10.7 10.2 9.7 9.1 8.37.5 11.1 10.7 10.3 9.7 9.1 8.4 7.6 sorbitan oleate Polyoxyl 35 castoroil 9.0 5.5 5.9 6.4 6.9 7.5 8.3 9.1 5.6 6.0 6.4 7.0 7.6 8.4 9.1 Soybeanlecithin 4.7 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.3 4.3 4.3 4.3 4.3 4.3 4.3Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 12 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-106 3-107 3-108 3-109 3-110 3-111 3-112 3-113 3-114 3-1153-116 3-117 3-118 3-119 3-120 Ethyl eicosapentaenoate 78 78 78 78 78 7878 78 78 78 78 78 78 78 78 Purified water 1.2 1.2 1.2 1.2 1.2 1.2 1.21.5 1.5 1.5 1.5 1.5 1.5 1.5 2.4 Polyoxyethylene (20) 11.1 10.7 10.3 9.79.1 8.4 7.6 10.3 9.9 9.5 9.0 8.4 7.7 7.0 9.8 sorbitan oleate Polyoxyl 35castor oil 5.6 6.0 6.4 7.0 7.6 8.4 9.1 5.1 5.5 5.9 6.4 7.0 7.7 8.4 4.9Soybean lecithin 4.1 4.1 4.1 4.1 4.1 4.1 4.1 5.1 5.1 5.1 5.1 5.1 5.1 5.14.9 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 13 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-121 3-122 3-123 3-124 3-125 3-126 3-127 3-128 3-129 3-1303-131 3-132 3-133 3-134 3-135 Ethyl eicosapentaenoate 78 78 78 78 78 7879 79 79 79 79 79 79 79 79 Purified water 2.4 2.4 2.4 2.4 2.4 2.4 0.60.6 0.6 0.6 0.6 0.6 0.6 0.9 0.9 Polyoxyethylene (20) 9.5 9.0 8.6 8.0 7.46.7 10.3 10.0 9.5 9.0 8.5 7.8 7.0 10.7 10.3 sorbitan oleate Polyoxyl 35castor oil 5.3 5.7 6.1 6.7 7.4 8.0 5.2 5.5 6.0 6.5 7.0 7.8 8.5 5.3 5.7Soybean lecithin 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.14.1 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 14 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-136 3-137 3-138 3-139 3-140 3-141 3-142 3-143 3-144 3-1453-146 3-147 3-148 3-149 3-150 Ethyl eicosapentaenoate 79 79 79 79 79 7979 79 79 79 79 79 79 79 79 Purified water 0.9 0.9 0.9 0.9 0.9 1.2 1.21.2 1.2 1.2 1.2 1.2 1.5 1.5 1.5 Polyoxyethylene (20) 9.8 9.3 8.7 8.0 7.310.2 9.8 9.4 8.9 8.3 7.7 7.0 10.0 9.6 9.2 sorbitan oleate Polyoxyl 35castor oil 6.2 6.7 7.3 8.0 8.7 5.1 5.5 5.9 6.4 7.0 7.7 8.3 5.0 5.4 5.8Soybean lecithin 4.1 4.1 4.1 4.1 4.1 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.54.5 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 15 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-151 3-152 3-153 3-154 3-155 3-156 3-157 3-158 3-159 3-1603-161 3-162 3-163 3-164 3-165 Ethyl eicosapentaenoate 79 79 79 79 79 7979 79 79 79 79 79 79 79 79 Purified water 1.5 1.5 1.5 1.5 1.8 1.8 1.81.8 1.8 1.8 1.8 2.4 2.4 2.4 2.4 Polyoxyethylene (20) 8.8 8.2 7.5 6.810.1 9.7 9.3 8.8 8.2 7.6 6.9 9.1 8.8 8.4 8.0 sorbitan oleate Polyoxyl 35castor oil 6.3 6.8 7.5 8.2 5.0 5.4 5.8 6.3 6.9 7.6 8.2 4.6 4.9 5.3 5.7Soybean lecithin 4.5 4.5 4.5 4.5 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.9 4.9 4.94.9 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 16 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-166 3-167 3-168 3-169 3-170 3-171 3-172 3-173 3-174 3-1753-176 3-177 3-178 3-179 3-180 Ethyl eicosapentaenoate 79 79 79 80 80 8080 80 80 80 80 80 80 80 80 Purified water 2.4 2.4 2.4 0.8 0.8 0.8 0.80.8 0.8 0.8 0.9 0.9 0.9 0.9 0.9 Polyoxyethylene (20) 7.5 6.9 6.2 9.4 9.18.7 8.2 7.7 7.1 6.4 9.9 9.5 9.1 8.6 8.1 sorbitan oleate Polyoxyl 35castor oil 6.2 6.9 7.5 4.7 5.0 5.4 5.9 6.4 7.1 7.7 4.9 5.3 5.7 6.2 6.7Soybean lecithin 4.9 4.9 4.9 5.1 5.1 5.1 5.1 5.1 5.1 5.1 4.3 4.3 4.3 4.34.3 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 17 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-181 3-182 3-183 3-184 3-185 3-186 3-187 3-188 3-189 3-1903-191 3-192 3-193 3-194 3-195 Ethyl eicosapentaenoate 80 80 80 80 80 8080 80 80 80 80 80 80 80 80 Purified water 0.9 0.9 1.0 1.0 1.0 1.0 1.01.0 1.0 1.2 1.2 1.2 1.2 1.2 1.2 Polyoxyethylene (20) 7.4 6.7 9.5 9.2 8.88.3 7.8 7.2 6.5 9.4 9.1 8.7 8.2 7.7 7.1 sorbitan oleate Polyoxyl 35castor oil 7.4 8.1 4.8 5.1 5.5 6.0 6.5 7.2 7.8 4.7 5.0 5.4 5.9 6.4 7.1Soybean lecithin 4.3 4.3 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.74.7 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 18 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-196 3-197 3-198 3-199 3-200 3-201 3-202 3-203 3-204 3-2053-206 3-207 3-208 3-209 3-210 Ethyl eicosapentaenoate 80 80 80 80 80 8080 80 80 80 80 80 80 80 80 Purified water 1.2 1.5 1.6 1.6 1.6 1.6 1.61.6 2.4 2.4 2.4 2.4 2.4 2.4 2.4 Polyoxyethylene (20) 6.4 9.5 9.1 8.7 8.27.7 7.1 6.4 8.3 8.0 7.7 7.3 6.8 6.3 5.7 sorbitan oleate Polyoxyl 35castor oil 7.7 4.7 5.0 5.4 5.9 6.4 7.1 7.7 4.2 4.5 4.8 5.2 5.7 6.3 6.8Soybean lecithin 4.7 4.3 4.3 4.3 4.3 4.3 4.3 4.3 5.1 5.1 5.1 5.1 5.1 5.15.1 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 19 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-211 3-212 3-213 3-214 3-215 3-216 3-217 3-218 3-219 3-2203-221 3-222 3-223 3-224 3-225 Ethyl eicosapentaenoate 81 81 81 81 81 8181 81 81 81 81 81 81 81 81 Purified water 0.6 0.6 0.6 0.6 0.6 0.6 0.60.9 0.9 0.9 0.9 0.9 0.9 0.9 1.2 Polyoxyethylene (20) 9.5 9.2 8.8 8.3 7.87.2 6.5 9.2 8.9 8.5 8.1 7.5 6.9 6.3 8.9 sorbitan oleate Polyoxyl 35castor oil 4.8 5.1 5.5 6.0 6.5 7.2 7.8 4.6 4.9 5.3 5.8 6.3 6.9 7.5 4.4Soybean lecithin 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.3 4.3 4.3 4.3 4.3 4.3 4.34.5 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 20 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex.Component 3-226 3-227 3-228 3-229 3-230 3-231 3-232 3-233 3-234 3-2353-236 3-237 3-238 3-239 3-240 Ethyl eicosapentaenoate 81 81 81 81 81 8181 81 81 81 81 81 81 81 81 Purified water 1.2 1.2 1.2 1.2 1.2 1.2 1.51.5 1.5 1.5 1.5 1.5 1.5 1.8 1.8 Polyoxyethylene (20) 8.6 8.2 7.8 7.3 6.76.0 8.5 8.2 7.9 7.5 7.0 6.4 5.8 8.2 7.9 sorbitan oleate Polyoxyl 35castor oil 4.8 5.1 5.5 6.0 6.7 7.3 4.3 4.6 4.9 5.3 5.8 6.4 7.0 4.1 4.4Soybean lecithin 4.5 4.5 4.5 4.5 4.5 4.5 4.7 4.7 4.7 4.7 4.7 4.7 4.7 4.94.9 Total 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

TABLE 21 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Component 3-2413-242 3-243 3-244 3-245 3-246 3-247 3-248 3-249 3-250 3-251 3-252 Ethyleicosapentaenoate 81 81 81 81 81 81 81 81 81 81 81 81 Purified water 1.81.8 1.8 1.8 1.8 2.4 2.4 2.4 2.4 2.4 2.4 2.4 Polyoxyethylene (20) 7.6 7.26.7 6.2 5.6 7.7 7.4 7.1 6.7 6.3 5.8 5.2 sorbitan oleate Polyoxyl 35castor oil 4.7 5.1 5.6 6.2 6.7 3.8 4.1 4.4 4.8 5.2 5.8 6.3 Soybeanlecithin 4.9 4.9 4.9 4.9 4.9 5.1 5.1 5.1 5.1 5.1 5.1 5.1 Total 100 100100 100 100 100 100 100 100 100 100 100

INDUSTRIAL APPLICABILITY

The self-emulsifying composition of the present invention is excellentin at least one out of the compatibility (appearance), theself-emulsifying property, the composition dispersibility, the emulsionstability and the absorbability, and it, as being absorbed rapidly evenif taken before meals, suppresses increase of serum TG after the meal.The self-emulsifying composition of the present invention is useful forincorporating in various foods, or as food for special dietary uses,food with health claims (food for specified health use and food withnutrient function claims), health food (supplement), or a pharmaceuticalproduct.

The self-emulsifying composition of the present invention has no or lowcontent of the polyhydric alcohol, and therefore, the composition isfree from the problem of softening and deformation of the capsule duringthe distribution or storage caused by the polyhydric alcohol. In otherwords, the self-emulsifying composition of the present invention isassociated with reduced risk of quality change.

The self-emulsifying composition of the present invention has thequality as a pharmaceutical product capable of being stored in a cold orhot location since the composition does not become cloudy or separatedeven if stored in low or high temperature environment.

1. A self-emulsifying composition comprising at least one compoundselected from the group consisting of ω3 polyunsaturated fatty acids andtheir pharmaceutically acceptable salts and esters as well as lecithinand/or a polyoxyethylene sorbitan fatty acid ester as an emulsifier,which upon administration to human satisfies at least one selected fromamong following (a) to (e) calculated by conducting correction bysubtracting plasma ω3 polyunsaturated fatty acid concentration beforethe administration: (a) maximum plasma ω3 polyunsaturated fatty acidconcentration is at least 50 μg/mL; (b) plasma ω3 polyunsaturated fattyacid concentration 2 hours after the administration is at least 20μg/mL; (c) time required to reach the maximum plasma ω3 polyunsaturatedfatty acid concentration (Tmax) is up to 6 hours; (d) area under thecurve of the plasma ω3 polyunsaturated fatty acid concentration at 0 to72 hours after the administration is at least 500 μg·hr/mL; and (e)blood ω3 polyunsaturated fatty acid concentration 24 hours after theadministration is 5 to 100 μg/mL.
 2. A self-emulsifying compositionaccording to claim 1 wherein the at least one compound selected from thegroup consisting of ω3 polyunsaturated fatty acids and theirpharmaceutically acceptable salts and esters in the composition to beadministered to human is 1000 mg to 10000 mg.
 3. A self-emulsifyingcomposition according to claim 1 wherein the ω3 polyunsaturated fattyacids and their pharmaceutically acceptable salts and esters in thecomposition to be administered to human are at least one member selectedfrom the group consisting of EPA and their pharmaceutically acceptablesalts and esters.
 4. A self-emulsifying composition according to claim 3wherein the EPA and their pharmaceutically acceptable salts and estersare an ethyl ester of EPA.
 5. A self-emulsifying composition accordingto claim 1 wherein when the composition is administered, the maximumplasma ω3 polyunsaturated fatty acid concentration calculated byconducting the correction by subtracting the plasma ω3 polyunsaturatedfatty acid concentration before the administration is at least 50 μg/mL,and the area under the curve of the plasma ω3 polyunsaturated fatty acidconcentration at 0 to 72 hours after the administration is at least 500μg·hr/mL.
 6. A self-emulsifying composition according to claim 1wherein, when the composition is administered under fasting, the maximumplasma ω3 polyunsaturated fatty acid concentration calculated byconducting the correction by subtracting the plasma ω3 polyunsaturatedfatty acid concentration before the administration is at least threetimes as high as the maximum plasma ω3 polyunsaturated fatty acidconcentration immediately after the meal, or the area under the curve ofthe plasma ω3 polyunsaturated fatty acid concentration at 0 to 72 hoursafter the administration is at least twice as large as the area underthe curve of the plasma ω3 polyunsaturated fatty acid concentrationimmediately after the meal.
 7. A self-emulsifying composition accordingto claim 1 wherein the composition contains lecithin and apolyoxyethylene sorbitan fatty acid ester as an emulsifier.
 8. Aself-emulsifying composition according to claim 1 wherein thecomposition further contains polyoxyethylene castor oil as anemulsifier.
 9. A self-emulsifying composition according to claim 1wherein the composition containing 1000 mg to 10000 mg of the at leastone compound selected from the group consisting of ω3 polyunsaturatedfatty acids and their pharmaceutically acceptable salts and esters isadministered once a day.
 10. A self-emulsifying composition according toclaim 1 wherein the composition contains water.